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. 2016 Apr 21;10:10. doi: 10.1186/s40246-016-0074-2

Organization, evolution and functions of the human and mouse Ly6/uPAR family genes

Chelsea L Loughner 1, Elspeth A Bruford 2, Monica S McAndrews 3, Emili E Delp 1, Sudha Swamynathan 1, Shivalingappa K Swamynathan 1,4,5,6,7,✉
PMCID: PMC4839075  PMID: 27098205

Abstract

Members of the lymphocyte antigen-6 (Ly6)/urokinase-type plasminogen activator receptor (uPAR) superfamily of proteins are cysteine-rich proteins characterized by a distinct disulfide bridge pattern that creates the three-finger Ly6/uPAR (LU) domain. Although the Ly6/uPAR family proteins share a common structure, their expression patterns and functions vary. To date, 35 human and 61 mouse Ly6/uPAR family members have been identified. Based on their subcellular localization, these proteins are further classified as GPI-anchored on the cell membrane, or secreted. The genes encoding Ly6/uPAR family proteins are conserved across different species and are clustered in syntenic regions on human chromosomes 8, 19, 6 and 11, and mouse Chromosomes 15, 7, 17, and 9, respectively. Here, we review the human and mouse Ly6/uPAR family gene and protein structure and genomic organization, expression, functions, and evolution, and introduce new names for novel family members.

Keywords: Ly6/uPAR family, LU domain, Three-finger domain, uPAR, Lymphocytes, Neutrophils

Introduction

The lymphocyte antigen-6 (Ly6)/urokinase-type plasminogen activator receptor (uPAR) superfamily of structurally related proteins is characterized by the LU domain, an 80 amino acid domain containing ten cysteines arranged in a specific spacing pattern that allows distinct disulfide bridges which create the three-fingered (3F) structural motif [1, 2]. Ly6/uPAR proteins were first identified in the mouse over 35 years ago using antisera against lymphocytes [3]. Human homologs were subsequently isolated, leading to the recognition that they represent a well-conserved family with wide-ranging expression patterns and important functions. The fully annotated human and mouse genomes contain 35 and 61 Ly6/uPAR family members, respectively. Research over the last decade has begun to unravel the important functions of the encoded proteins. In this review, we provide an overview of the Ly6/uPAR gene family and their genomic organization, evolution, as well as functions, and provide a nomenclature system for the newly identified members of this family.

Inclusion and approved nomenclature for novel Ly6/uPAR family members

Although Ly6/uPAR family members are related by their structure, absence of a uniform naming convention resulted in arbitrary nomenclature for these genes as they were discovered. As many of the currently approved gene symbols for Ly6/uPAR family members (e.g., CD59 and PLAUR) have been widely used in the scientific literature for many years, we have refrained from a family-wide attempt to standardize their well-established names, avoiding the potential for additional confusion. In compiling this update, we came across many novel members of the Ly6/uPAR gene family, especially in the mouse genome, that did not yet have a systematic name. We named these novel family members in line with the Ly6/uPAR genes that they are most related to, based on a phylogenetic analysis (see below) using either the established LY6/Ly6# root for those that fell within the LY6 clades, or the LYPD/Lypd# (LY6/PLAUR domain-containing) root for those outside the LY6 clades. The new symbols for these genes (1 human and 18 mouse), approved by the HGNC (HUGO Gene Nomenclature Committee) [4, 5] and MGNC (Mouse Genomic Nomenclature Committee) [6], are listed in Tables 1 and 2, respectively. We use the newly approved names for these genes in the rest of this update. HGNC have also created a gene family web-page for the human Ly6/uPAR family members (http://www.genenames.org/cgi-bin/genefamilies/set/1226).

Table 1.

Name, chromosomal location, number of exons, and LU domains for human Ly6/uPAR family genes

Approved gene symbol (NCBI accession #) Gene name Alias(es) Genomic location Number of
Exons LU Domains
ACRV1
(NP_001603.1)		 Acrosomal vesicle protein 1 SP-10; SPACA2; D11S4365 11q24.2 5 1
CD177
(BAE93254.1)		 CD177 molecule (Human Neutrophil Alloantigen 2A) NB1; PRV1; HNA2A; PRV-1; HNA-2a; NB1 GP 19q13.2 9 2
CD59
(CAG46523.1)		 CD59 molecule, complement regulatory protein 1 F5; EJ16; EJ30; EL32; G344; MIN1; MIN2; MIN3; MIRL; HRF20; MACIF; MEM43; MIC11; MSK21; 16.3A5; HRF-20; MAC-IP; p18-20 11p13 5 1
GML
(EAW82296.1)		 Glycosylphosphatidylinositol anchored molecule like LY6DL 8q24.3 5 1
GPIHBP1
(AAH35810.2)		 Glycosylphosphatidylinositol anchored high density lipoprotein-binding protein 1 HYPL1D; GPI-HBP1 8q24.3 4 1
LY6D
(AAH31330.1)		 Lymphocyte antigen 6 complex, locus D E48; Ly-6D 8q24 3 1
LY6E
(AAH03392.1)		 Lymphocyte antigen 6 complex, locus E RIGE; SCA2; RIG-E; SCA-2; TSA-1 8q24.3 4 1
LY6G5B
(CAC85543.1)		 Lymphocyte antigen 6 complex, locus G5B G5b; C6orf19 6p21.3 3 1
LY6G5C
(CAC85542.1)		 Lymphocyte antigen 6 complex, locus G5C G5C; NG33; C6orf20; LY6G5CA; LY6G5CB 6p21 3 1
LY6G6C
(EAX03491.1)		 Lymphocyte antigen 6 complex, locus G6C G6c; NG24; C6orf24 6p21 3 1
LY6G6D
(CAC85540.1)		 Lymphocyte antigen 6 complex, locus G6D G6D; NG25; LY6-D; MEGT1; C6orf23 6p21.3 3 1
LY6G6F
(AAI37213.1)		 Lymphocyte antigen 6 complex, locus G6F G6f; NG32; LY6G6D; C6orf21 6p21.33 6 1
LY6H
(BAA34115.1)		 Lymphocyte antigen 6 complex, locus H NMLY6 8q24.3 4 1
LY6K
(AAI17145.1)		 Lymphocyte antigen 6 complex, locus K CT97; ly-6 K; URLC10; HSJ001348 8q24.3 3 1
LY6L a
(XP_011544859.1)		 Lymphocyte antigen 6 complex, locus L LOC101928108 8q24.3 5 1
LYNX1
(NP_803429.1)		 Ly6/neurotoxin 1 8q24.3 4 1
LYPD1
(EAX11675.1)		 Ly6/PLAUR domain containing 1 PHTS; LYPDC1; LYNX2 2q21.2 3 1
LYPD2
(EAW82307.1)		 Ly6/PLAUR domain containing 2 LYPDC2; UNQ430 8q24.3 3 1
LYPD3
(EAW57190.1)		 Ly6/PLAUR domain containing 3 C4.4A 19q13.31 5 2
LYPD4
(AAH34629.1)		 Ly6/PLAUR domain containing 4 Sperm Membrane Receptor 19q13.2 5 1
LYPD5
(EAW57232.1)		 Ly6/PLAUR domain containing 5 PRO4356 19q13.31 5 1
LYPD6
(AAH47013.1)		 Ly6/PLAUR domain containing 6 2q23.2 5 1
LYPD6B
(AAH18203.1)		 Ly6/PLAUR domain containing 6B CT116; LYPD7 2q23.2 7 1
LYPD8
(NP_001278212.1)		 Ly6/PLAUR domain containing 8 1q44 7 1
PATE1
(AAI07045.1)		 Prostate and testis expressed 1 PATE 11q24.2 5 1
PATE2
(AAI44527.1)		 Prostate and testis expressed 2 PATE-M; UNQ3112; C11orf38 11q24.2 6 1
PATE3
(NP_001123355.3)		 Prostate and testis expressed 3 HEL-127; PATE-DJ 11q24.2 3 1
PATE4
(NP_001138346.1)		 Prostate and testis expressed 4 PATE-B 11q24.2 3 1
PINLYP
(NP_001180550.1)		 Phospholipase A2 inhibitor and Ly6/PLAUR domain containing 19q13.31 6 1
PLAUR
(CAG33233.1)		 Plasminogen activator, urokinase receptor CD87; UPAR; URKR; U-PAR 19q13 7 3
PSCA
(AAH65183.1)		 Prostate stem cell antigen PRO232 8q24.2 3 1
SLURP1
(AAT01436.1)		 Secreted Ly6/PLAUR domain containing 1 ARS; MDM; ANUP; ArsB; LY6LS 8q24.3 3 1
SLURP2
(NP_803253.1)		 Secreted Ly6/PLAUR domain containing 2 LYNX1, isoform B precursor 8q24.3 4 1
SPACA4
(AAQ88753.1)		 Sperm acrosome associated 4 SAMP14 19q13.33 1 1
TEX101
(EAW57189.1)		 Testis expressed 101 SGRG; CT131; GTPR867; NYD-SP8; PRO1884; SPATA44; TES101RP 19q13.31 9 1
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aNovel gene named in this study

Table 2.

Name, chromosomal location, number of exons and LU domains for mouse Ly6/uPAR family genes

Approved gene symbol (NCBI Accession #) Gene name Alias(es) Genomic location Number of
Exons LU domains
Acrv1
(EDL25409.1)		 Acrosomal vesicle protein 1 Msa63; SP-10 9 A4 4 1
Cd177
(AAH27283.1)		 CD177 antigen Pdp3; 1190003K14Rik 7 A3 17 4
Cd59a
(AAL04433.1)		 CD59a antigen Cd59; AA987121; protectin 2 54.53 cM 6 1
Cd59b
(AAL04434.1)		 CD59b antigen 2 E2 9 1
Gml
(CAB57316.1)		 Glycosylphosphatidylinositol anchored molecule like HemT3; EG625599 15 D3 5 1
Gml2
(AAI19338.1)		 Glycosylphosphatidylinositol anchored molecule like 2 HemT; Hemt1; 1700057K19Rik 15 D3 7 1
Gpihbp1
(NP_081006.1)		 Glycosylphosphatidylinositol anchored high density lipoprotein-binding protein 1 GPI-HBP1; 1110002J19Rik 15 E1 4 1
Ly6a
(AAH02070.1)		 Lymphocyte antigen 6 complex, locus A TAP; Sca1; Sca-1; Ly-6A.2; Ly-6A/E; Ly-6E.1 15 34.29 cM 4 1
Ly6a2 a
(XP_006543305.1)		 Lymphocyte antigen 6 complex, locus A2 Ly6A-2/E-1, I830127L07Rik 15 D3 4 1
Ly6c1
(AAH10764.1)		 Lymphocyte antigen 6 complex, locus C1 Ly6c; Ly-6C; Ly-6C1; AA682074; AA959465 15 34.29 cM 6 1
Ly6c2
(NP_001092687.1)		 Lymphocyte antigen 6 complex, locus C2 Ly-6C2; Ly-6C.2 15 D3 4 1
Ly6d
(EDL29445.1)		 Lymphocyte antigen 6 complex, locus D Thb; Ly61; Ly-61 15 D3 3 1
Ly6e
(CAJ18452.1)		 Lymphocyte antigen 6 complex, locus E Ly67; Tsa1; RIG-E; Sca-2; TSA-1 15 D3 5 1
Ly6f
(EDL29474.1)		 Lymphocyte antigen 6 complex, locus F 15 D3 4 1
Ly6g
(NP_001297367.1)		 Lymphocyte antigen 6 complex, locus G Gr1; Gr-1; Ly-6G 15 D3 4 1
Ly6g2 a(AAH25446.1) Lymphocyte antigen 6 complex, locus G2 BC025446 15 D3 6 1
Ly6g5b
(CAC85549.1)		 Lymphocyte antigen 6 complex, locus G5B 17 B1 3 1
Ly6g5c
(CAC85548.1)		 Lymphocyte antigen 6 complex, locus G5C G5c; NG33 17 B1 3 1
Ly6g6c
(AAI16367.1)		 Lymphocyte antigen 6 complex, locus G6C G6c; NG24; AU016360; 1110003M04Rik 17 B1 3 1
Ly6g6d
(CAC85545.1)		 Lymphocyte antigen 6 complex, locus G6D G6d; G6f; NG25; NG32; MEGT1; A930024F17Rik 17 B1 4 1
Ly6g6e
(AAI38778.1)		 Lymphocyte antigen 6 complex, locus G6E G6e; 2310011I02Rik 17 B2 3 1
Ly6g6f
(AAI72069.1)		 Lymphocyte antigen 6 complex, locus G6F CJ068215 17 B1 6 1
Ly6g6g a(EDL29446.1) Lymphocyte antigen 6 complex, locus G6G D730001G18Rik 15 D3 3 1
Ly6h
(AAH28758.1)		 Lymphocyte antigen 6 complex, locus H 15 E1 6 1
Ly6i
(AAI45088.1)		 Lymphocyte antigen 6 complex, locus I Ly-6I; Ly-6 M; AI789751 15 D3 6 1
Ly6k
(AAH49723.1)		 Lymphocyte antigen 6 complex, locus K mLy-6 K; 2410015A16Rik; 3110035B01Rik 15 4 1
Ly6l a
(XP_006521679.1)		 Lymphocyte antigen 6 complex, locus L Gm20654 15 34.37 cM 3 1
Ly6m a(EDL29458.1) Lymphocyte antigen 6 complex, locus M 2010109I03Rik 15 D3 3 1
Lynx1
(AAF16899.1)		 Ly6/neurotoxin 1 AI838844 15 D3 4 1
Lypd1
(AAH58599.1)		 Ly6/PLAUR domain containing 1 Lynx2; Lypdc1; AI853408; 2700050C12Rik; C530008O16Rik 1 E3 6 1
Lypd2
(AAI32410.1)		 Ly6/PLAUR domain containing 2 VLL; Lypdc2; 0610005K03Rik 15 E1 4 1
Lypd3
(AAH16549.1)		 Ly6/PLAUR domain containing 3 C4.4a; 2310061G07Rik 7 A3 5 2
Lypd4
(AAH49744.1)		 Ly6/PLAUR domain containing 4 4933400F01Rik 7 A3 5 1
Lypd5
(AAI07188.1)		 Ly6/PLAUR domain containing 5 2210003I03Rik 7 A3 5 1
Lypd6
(AAH70462.1)		 Ly6/PLAUR domain containing 6 E130115E03Rik 2 C1.1 7 1
Lypd6b
(AAI26944.1)		 Ly6/PLAUR domain containing 6B AW049525; 2310010M24Rik 2 C1.1 14 1
Lypd8
(NP_001077353.1)		 Ly6/PLAUR domain containing 8 2210415F13Rik 11 B1.3 8 1
Lypd9 a(AAH48595.1) Ly6/PLAUR domain containing 9 4930504O13Rik
Gm524 		11 B1.3 4 1
Lypd10 a(BC049730.1) Ly6/PLAUR domain containing 10 BC049730 7 A3 8 1
Lypd11 a(NP_808261.1) Ly6/PLAUR domain containing 11 Gm4763,
EG210155 		7 A3 9 1
Pate1
(NP_001186882.1)		 Prostate and testis expressed 1 Pate 9 A4 5 1
Pate2
(NP_001028593.1)		 Prostate and testis expressed 2 Gm846; Pate-M; mANLP1 9 A4 10 1
Pate3
(NP_001161064.1)		 Prostate and testis expressed 3 Pate-dj 9 A4 3 1
Pate4
(AAI20767.1)		 Prostate and testis expressed 4 Svs7; Pate-B; 9530004K16Rik 9 A4 4 1
Pate5 a
(NP_084139.1)		 Prostate and testis expressed 5 9230110F15Rik, Pate-A, mANLP3 9 A4 3 1
Pate6 a
(NP_080869.1)		 Prostate and testis expressed 6 D730048I06Rik, Pate-C, mANLP2 9 A4 3 1
Pate7 a
(NP_001161145.1)		 Prostate and testis expressed 7 Pate-E, Gm17727 9 A4 3 1
Pate8 a
(NP_001161056.1)		 Prostate and testis expressed 8 Pate-G,
Gm17689 		9 A4 3 1
Pate9 a
(NP_001028955.1)		 Prostate and testis expressed 9 Pate-H, EG434396, Gm5615 9 A4 3 1
Pate10 a
(ACD81927.1)		 Prostate and testis expressed 10 Pate-N, Gm17677 9 A4 3 1
Pate11 a
(ACD81928.1)		 Prostate and testis expressed 11 Pate-P, Gm9513 9 A4 4 1
Pate12 a
(NP_001161058.1)		 Prostate and testis expressed 12 Pate-Q, EG639025, Gm7257 9 A4 4 1
Pate13 a
(XP_006510783.1)		 Prostate and testis expressed 13 9230113P08Rik 9 A4 3 1
Pate14 a
(NP_001028497.1)		 Prostate and testis expressed 14 A630095E13Rik, Gm191; Sslp1 9 A4 4 1
Pinlyp
(NP_001032220.1)		 Phospholipase A2 inhibitor and Ly6/PLAUR domain containing 2310033E01Rik 7 A2-A3 6 1
Plaur
(NP_035243.1)		 Plasminogen activator, urokinase receptor Cd87; uPAR; u-PAR 7 A3 11 3
Psca
(EDL29439.1)		 Prostate stem cell antigen 2210408B04Rik 15 D3 3 1
Slurp1
(EDL29441.1)		 Secreted Ly6/PLAUR domain containing 1 ARS; ArsB; Slurp-1; AI415082; 1110021N19Rik 15 D3 3 1
Slurp2 a
(AAI15612.1)		 Secreted Ly6/PLAUR domain containing 2 2300005B03Rik 15 D3 3 1
Spaca4
(AAH48608.1)		 Sperm acrosome associated 4 Samp14; AV043694; 1700008E09Rik 7 B4 1 1
Tex101
(AAH48475.1)		 Testis expressed 101 AI429076; TES101RP; 1700008H15Rik 7 A3 6 1
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aNovel genes named in this study

Genomic organization of the Ly6/uPAR gene family

The Ly6/uPAR gene family currently includes 35 well-characterized human members, while the mouse gene family is considerably larger with 61 genes. Information including the name, chromosomal location, numbers of exons and LU domains for human and mouse family members is summarized in Tables 1 and 2, respectively. Twelve human Ly6 genes are clustered together within a short span of about 500 kb on chromosome 8 (8q24) (moving outward from the center of the chromosome: PSCA, LY6K, SLURP1, LYPD2, LYNX1/SLURP2, LY6D, GML, LY6E, LY6L, LY6H, and GPIHBP1) (http://genome-euro.ucsc.edu). The syntenic region on mouse Chromosome 15 (15D3-15E1) contains Psca, Slurp1, Lypd2, Slurp2, Lynx1, Ly6d, Ly6g6g, Ly6k, Gml, Gml2, Ly6m, Ly6e, Ly6i, Ly6a, Ly6c1, Ly6c2, Ly6a2, Ly6g, Ly6g2, Ly6f, Ly6l, Ly6h, and Gpihbp1. Other smaller clusters are seen on human chromosome 19 (19q13) (LYPD4, CD177, TEX101, LYPD3, PINLYP, PLAUR, LYPD5, and SPACA4 with syntenic region on mouse Chromosome 7 containing Lypd5, Plaur, Pinlyp, Lypd3, Tex101, Lypd10, Lypd11, Cd177, Lypd4, and Spaca4), human chromosome 11 (11q24.2) (ACRV1, PATE1, PATE2, PATE3, and PATE4 with syntenic region on mouse Chromosome 9 containing Pate4, Pate2, Pate13, Pate3, Pate1, Pate10, Pate7, Pate6, Pate5, Pate12, Pate11, Pate9, Pate8, Pate14, and Acrv1), and human chromosome 6 (6p21) (LY6G6C, LY6G6D, LY6G6F, LY6G5C, and LY6G5B with syntenic region in the MHC class III region of the mouse Chromosome 17 containing Ly6g6c, Ly6g5c, Ly6g5b, Ly6g6d, Ly6g6f, and Ly6g6e), while the remaining family members are found on other chromosomes (Tables 1 and 2).

Typical Ly6/uPAR gene structure

Ly6/uPAR family members typically contain one LU domain, with the exception of LYPD3 [7] and CD177 [8] which contain two, and PLAUR [9], which contains three direct repeats of the LU domain (Tables 1 and 2). The mouse Cd177 differs from its human ortholog in that it contains four direct repeats of the LU domain. A typical Ly6/uPAR family gene consists of three exons and two introns (Fig. 1a), with the signal peptide being encoded in the first exon. The mature polypeptide is encoded by the last two exons, with the GPI-anchor domain encoded by the third exon.

Fig. 1.

Fig. 1

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Structure of a typical Ly6/UPAR family gene and alignment of amino acid sequences of selected LU domains. a Structure of a typical LY6/UPAR family gene, showing three exons (E-1, E-2 and E-3), two introns (I-1 and I-2), and the location of signal peptide as well as GPI-anchor domain. b Alignment of LU domain amino acid sequences of selected human LY6/UPAR proteins. GPI-anchored (top) and secreted (bottom) proteins are clustered together, with an empty line in between. Alignments were performed using ProbCons in Bioinformatics toolkit provided by Max-Planck Institute for Developmental Biology (http://toolkit.tuebingen.mpg.de). Conserved cysteines linked by non-variant disulfide bridges are highlighted in similar colors. Isoforms are denoted with a dash and the isoform name (e.g. LY6G6D-A). LYNX1-C and SLURP2 are precursor forms of the final protein. NTS, Non-translated sequence

Based on their subcellular localization, Ly6/uPAR family members are further subdivided into two groups: membrane-tethered (through a GPI-anchor domain) or secreted (lacking the GPI-anchor domain). GPI-anchored Ly6/uPAR family members tend to congregate on lipid rafts on the cell surface, which promotes their interactions with other proteins. A fraction of the GPI-anchored Ly6/uPAR family proteins such as PLAUR are secreted after their GPI-anchor domain is proteolytically cleaved [10–12]. Experimental evidence supports the presence of a GPI-anchoring signal peptide in a majority of Ly6/uPAR family members, while it is absent in a few (Table 3). For those with no experimental evidence, the GPI-anchor signal predictor ‘PredGPI’ program (http://gpcr.biocomp.unibo.it/predgpi/) [13] predicted the presence of a GPI-anchor signal within mouse and human LYPD8 and LY6L, and in mouse LYPD10, LYPD11, LYPD9, LY6F, and LY6M, while predicting its absence in mouse and human LYPD4, LY6G6F, and PINLYP, and in mouse GML2 and LY6G6 (Table 3).

Table 3.

Expression patterns, interacting factors and cellular functions of mouse Ly6/uPAR family proteins

Approved protein symbol Human ortholog? Expression pattern Interacting factors Cellular function Gene knockout? GPI-anchor? References
ACRV1 Yes Spermatazoa (acrosomes) TARDBP (TDP-43) Sperm-oolemma binding/penetration No No [29, 31, 109–111]
CD177 Yes Neutrophils PR3, PECAM1 Neutrophil activation Yes Yes [46, 47, 112–114]
CD59A No Neurons, T cells, splenic macrophages, spermatids MAC Complex Complement inhibitor Yes Yes [115–118]
CD59B Yes (as CD59) Lymphocytes, granulocytes, platelets, erythrocytes, activated T cells, spermatazoa, splenic macrophages, mature spermatozoa C8, C9 Complement inhibition, cell-cell adhesion Yes Yes [17, 48, 56, 67, 118–120]
GML Yes Cancer cells TRP53 Apoptosis No Yes [121, 122]
GML2 No Hematopoetic stem cells Unknown Unknown No Predicted No [123]
GPIHBP1 Yes Capillary endothelial cells LPL Chylomicron processing, LPL transport Yes Yes [62, 63, 124]
LY6A No Hematopoetic stem cells, B cells, T cells, DCs IFN-γ, MMPs T cell activation and proliferation controller Yes Yes [28, 125–129]
LY6A2 No Unknown Unknown Unknown No Predicted Yes
LY6C1 No T cells, NK cells, monocytes, neutrophils, DCs, bone marrow myeloid cells Type I and II interferons, LFA-1 CD8+ T cell migration No Yes [28]
LY6C2 No T cells, NK cells, monocytes, neutrophils, DCs, bone marrow myeloid cells Type I and II interferons, LFA-1 CD8+ T cell migration No Yes [28]
LY6D Yes Keratinocytes, B cells Camptothecin, mitomycin C, carboplatin, hydroxyurea, aphidicolin Cell adhesion, B cell specification No Yes [130–134]
LY6E Yes Myeloid cells, thymocytes Retinoic acid, INF1 Monocyte inhibitor, T cell development No Yes [135–139]
LY6F No Non-lymphoid tissues Unknown Unknown No Predicted Yes [140]
LY6G No Neutrophils, granulocytes LTB4, β2-integrins Neutrophil recruitment No Yes [28, 109, 141]
LY6G2 No Unknown Unknown Unknown No Predicted No
LY6G5B Yes Stomach, placenta Unknown Unknown No No [142, 143]
LY6G5C Yes Testis, fetal liver/spleen/retina/heart/thymus, MS lesions, germinal center B cells, carcinoid lung Unknown Hematopoietic cell differentiation No No [142, 143]
LY6G6C Yes Fibroblasts Unknown Filipodia functions No Yes [142, 143]
LY6G6D Yes Fibroblasts Unknown Filipodia functions No Yes [142, 143]
LY6G6E No Undifferentiated megakaryocyte-like cells Unknown α4β2 potentiator, cell adhesion and migration No Yes [105, 142]
LY6G6F Yes K562 acute myeloblastic leukemia cells GRB2, GRB7 Unknown No Predicted No [144]
LY6G6G No Unknown Unknown Unknown No Predicted No
LY6H Yes Exocrine and endocrine epithelial cells, CNS Unknown Unknown No Yes [145, 146]
LY6I No Monocytes, granulocytes, CD19+ B cells, thymocytes and T cells Unknown Unknown No Yes [28, 147]
LY6K Yes Keratinocytes, squamous cell carcinomas JUND, FOSL1, RAS Invasive cell metastasis Yes Yes [148–152]
LY6L Yes Unknown Unknown Unknown No Predicted Yes
LY6M No Unknown Unknown Unknown No Predicted Yes
LYNX1 Yes CNS neurons α4β2 and α7 nAChRs nAChR modulator Yes Yes [25, 66, 73, 153]
LYPD1 Yes Airway epithelial cells, embryonic tissue, CNS and PNS neurons α4β2, α4β4, and α7 nAChRs α7 nAChR modulator, tumor suppression Yes Yes [103, 104, 154, 155]
LYPD2 Yes Unknown α4β2 nAChRs nAChR Modulator No Yes [105]
LYPD3 Yes Stratum spinosum keratinocytes, cancer cells α6β4, MMP14 Metastasis, EMT, wound healing No Yes [156–160]
LYPD4 Yes Unknown Unknown Unknown No Predicted No
LYPD5 Yes Stratum granulosum keratinocytes AP-1 Unknown No Yes [156, 161]
LYPD6 Yes Ubiquitously WNT3A Tumor suppression No Yes [162–164]
LYPD6B Yes Testis, lung, stomach, prostate AP-1 PKC signal transduction pathway No Yes [165]
LYPD8 Yes Unknown Unknown Unknown No Predicted Yes
LYPD9 No Unknown Unknown Unknown No Predicted Yes
LYPD10 No Unknown Unknown Unknown No Predicted Yes
LYPD11 No Unknown Unknown Unknown No Predicted Yes
PATE1 Yes Leydig cells, testicular germ cells, prostatic epithelial cells principle cells, spermatazoa, INCA1 Spermatazoa/egg fusion and penetration, spermatazoa motility No No [29, 32, 166–168]
PATE2 Yes Spermatazoa, testicular germ cells, neuronal tissue nAChR nAChR modulator No No [29, 31]
PATE3 Yes Testis nAChR nAChR modulator No No [29]
PATE4 Yes Spermatazoa, prostatic apical epithelial cells, spinal cord tissue α7 nAChR nAChR modulator Yes No [29, 33]
PATE5 No Male reproductive organs Androgens, lumicrine testicular factors Unknown No No [29, 30]
PATE6 No Male reproductive organs Androgens nAChR regulator No No [29, 30]
PATE7 No Male reproductive organs Androgens Unknown No No [29, 30]
PATE8 No Male reproductive organs, skeletal muscle Androgens Unknown No No [29, 30]
PATE9 No Male reproductive organs Unknown Unknown No No [29, 30]
PATE10 No Male reproductive organs Androgens, lumicrine testicular factors Unknown No No [29, 30]
PATE11 No Placenta α4β2 nAChR α4β2 nAChR regulator No No [29, 30]
PATE12 No Placenta Unknown Unknown No No [29, 30]
PATE13 No Male reproductive organs Androgens Unknown No No [29]
PATE14 No Luminal epithelium of seminal vesicles Androgens Unknown No No [169]
PINLYP Yes Unknown Unknown Unknown No Predicted No
PLAUR Yes Airway epithelial cells, trophoblast cells, cancerous cells, HUVEC, pan-epithelial uPA, Mac-1, caveolin, SERPINE1, vitronectin, kininogen, thrombospondin, α2-macroglobulin receptor, MRC2, cation-independent mannose 6-phosphate/insulin-like growth factor II receptor Fibrinolysis, matrix remodeling, cell migration, growth factor activation, integrin regulation, tumor cell invasion, cell adhesion Yes Yes [23, 170–185]
PSCA Yes Prostate basal cells, epithelial cells of prostate, urinary bladder, kidney, skin, esophagus, stomach, and placenta, cortical cells SNAI2, α4 nAChR Tumor suppression, oncogene, nAChR modulator Yes Yes [26, 57–59, 61, 150, 186–188]
SLURP1 Yes Keratinocytes, mucocutaneous and aerodigestive epithelia, some C-fiber neurons α7 nAChR, KLF4 Tumor suppression, nAChR modulator Yes No [20, 76, 79, 94, 99, 189–192]
SLURP2 Yes Oral and epidermal keratinocytes α3 nAChR nAChR modulator, blocks apoptosis Yes No [99–102, 193]
SPACA4 Yes Spermatazoa Unknown Spermatazoa-egg binding/fusion No Yes [194]
TEX101 Yes Spermatazoa, cancerous tissues Progesterone, PLAU Spermatazoaatogenesis, spermatazoa-egg interaction, protease suppressor Yes Yes [151, 195–198]
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Structure of the LU domain

The Ly6/uPAR family members have a well-conserved LU domain with a characteristic three-finger structure formed by disulfide bridges connecting the conserved cysteine residues in a specific pattern. LU domains are topologically similar to the three-finger structure of snake venom neurotoxins, which have three β-sheet loops fixed in space by virtue of their unique disulfide bridges. The structure of the extracellular region of CD59 was first solved by 2D NMR methods [14, 15] and further refined by crystallography [16] revealing it to be a flat, disk-shaped molecule consisting of a two-stranded beta-sheet finger loosely packed against a protein core formed by a three-stranded beta-sheet and a short helix.

Alignment of LU domain amino acid sequences of selected human LY6/UPAR proteins performed using ProbCons (http://toolkit.tuebingen.mpg.de) revealed the location of conserved cysteines (Fig. 1b). Five well-conserved disulfide bridges between cysteine pairs 3 and 26, 6 and 13, 19 and 39, 45 and 63, and 64 and 69 stabilize the hydrophobic core, from which three β-sheet-based fingers protrude (Fig. 1b). The sequence of the amino acids exposed at the tips of each finger as well as the length of each of the fingers is variable, providing the three-finger motif with the flexibility for a wide range of intermolecular interactions. In addition to the LU domain, Ly6/uPAR family proteins possess a well-conserved LeuXxxCysXxxXxxCys motif at the amino-terminus and CysCysXxxXxxXxxXxxCysAsn motif at the carboxyl-terminus (Fig. 1b). Functional relevance of these motifs is not yet known.

Most Ly6/uPAR family proteins maintain the ten cysteines characteristic of the LU domain, with some notable exceptions. In PLAUR, which consists of three LU domains (designated D1, D2 and D3), only domain D2 is fully intact with ten cysteines, while domains D1 and D3 have seven and eight cysteines, respectively. Isoforms of proteins such as human LY6G5C maintain conservation throughout the LU domain in almost every isoform. In contrast, different isoforms of human LYNX1 maintain the necessary cysteines, but little else is conserved (Fig. 1b).

Expression of Ly6/uPAR family genes

The expression pattern, interacting factors, and cellular functions of the mouse and human Ly6/uPAR family members are summarized in Table 3. Expression of Ly6/uPAR proteins is (i) widespread and variable across diverse cell types and tissues, (ii) tightly regulated in a spatiotemporal manner, and (iii) often correlated with cellular differentiation. Although the Ly6/uPAR family protein structures are well-conserved across species, their expression patterns tend to vary, indicating divergence among their regulatory networks. Many Ly6/uPAR family members are expressed in hematopoietic precursors in a lineage-specific fashion making them useful cell surface markers for leukocytes, facilitating identification of individual leukocyte subgroups [17–19]. For example, mouse myeloid differentiation marker LY6G (also called Gr-1) is expressed by the myeloid lineage cells in a developmentally regulated manner in the bone marrow. Anti-LY6G antibodies are routinely used to identify neutrophils in the mouse but not humans as there is no human ortholog for Ly6g. Ly6/uPAR family members are generally upregulated during inflammatory conditions or infections and in cancerous cells, with a notable exception of SLURP1, which is invariably downregulated in pro-inflammatory conditions [9, 20–24].

Functions of Ly6/uPAR family proteins

Commensurate with their varied expression patterns, Ly6/uPAR proteins have a wide range of functions in cell proliferation, migration, cell-cell interaction, immune cell maturation, macrophage activation, and cytokine production. They typically exert their influence by targeting nicotinic acetylcholine receptors (nAChRs) (reviewed in [1]). GPI-anchored Ly6/uPAR proteins lacking a cytoplasmic tail are unable to directly participate in intracellular signaling but can initiate signaling by interacting with other transmembrane proteins. Such interactions of GPI-anchored proteins are further facilitated by their tendency to congregate in lipid rafts on the cell surface, where other signaling molecules also are enriched. While GPI-anchored Ly6/uPAR proteins control signaling through interaction with their ligand(s), secreted Ly6/uPAR proteins may serve as agonists for other receptors including nAChR and/or competing scavengers of their ligands [1, 20, 21, 25–27]. Many Ly6/uPAR family members have a prominent role in neutrophils (Table 3) [28]. Below, we summarize the functions of a few well-studied members.

Prostate and testis expressed genes

Human chromosome 11 contains 5 prostate and testis expressed (PATE) genes while the syntenic region on murine Chromosome 9 contains 15 genes [29]. Recent evidence demonstrates that PATE proteins are much more predominantly expressed in the epididymis with a significantly lower expression in the prostate and testis, suggesting that their names are misnomers [30]. PATE proteins secreted by epithelial cells to the epididymal lumen facilitate spermatozoan maturation as they leave the testis and travel through the epididymis. PATE proteins localized in the sperm head assist in sperm-oolemma fusion and penetration [31]. Defects in PATE1 result in decreased sperm motility in aged men and young asthenozoospermia patients, revealing the molecular basis for the decline in sperm quality with age [32]. PATE4 is abundantly expressed in the mouse prostate, spermatozoa, and seminal vesicles. Pate4−/− mice remain fertile and do not display any histological abnormalities [33]. PATE proteins are also expressed in neuron-rich tissues, where they function by modulating nAChR activities [29].

Plasminogen activator, urokinase receptor

Also known as the urokinase-type plasminogen activator receptor (uPAR), plasminogen activator, urokinase receptor (PLAUR) is the most well-studied family member [9]. It is widely expressed in different cell types and plays a key regulatory role in cell surface plasminogen activation, influencing many normal and pathologic processes [9, 23]. PLAUR consists of three direct repeats of the LU domain, which together bind urokinase-type plasminogen activator (PLAU/uPA) in both the pro-protein and mature forms. PLAUR (i) expression is regulated by KLF4 [34] and is upregulated in cancer cells [35, 36] and in response to pro-inflammatory conditions [37], (ii) facilitates neutrophil recruitment in response to bacterial infection [38], (iii) facilitates clearance of Borrelia infection [39], and (iv) interacts with multiple partners including vitronectin and different integrins. Although the bulk of PLAUR exists as GPI-anchored, some of it is known to be secreted as “soluble uPAR” (suPAR), the expression level of which is correlated with disease conditions [10–12, 40].

PLAUR is a multi-functional protein with important roles in regulating cell-matrix interaction, motility, and immune response. PLAUR expression levels directly correlate with the invasive potential of endometrial carcinomas, suggesting that it is a valuable prognostic marker for aggressive endometrial tumors [35]. PLAUR expression is normally low in healthy glomeruli and is elevated in glomeruli from individuals with focal segmental glomerulosclerosis, consistent with its role in regulating renal permeability [41]. PLAUR is required for neutrophil recruitment into alveoli and lungs in response to S. pneumoniae infection [42]. Plaur−/− macrophages display an enhanced ability to engulf wild-type neutrophils, but Plaur−/− neutrophils do not, suggesting that PLAUR plays an essential role in recognition and clearance of neutrophils [43]. Plaur−/− mice exhibit abnormal interneuron migration from the ganglionic eminence, and reduced interneurons in the frontal and parietal cortex [44, 45].

CD177

Expressed by neutrophils, neutrophilic metamyelocytes, and myelocytes, CD177 mediates neutrophil migration across the endothelium by binding PECAM1 (CD31). Anti-CD177 antibodies inhibit neutrophil transmigration across the endothelial monolayer, potentially by interfering with an interaction between CD177 and PECAM1 [46]. Mutations in CD177 or its dysregulated expression are associated with myeloproliferative diseases, secondary to a gain-of-function mutation in JAK2 [8]. Exposure of human neutrophils to pulmonary endotoxin results in strong upregulation of CD177 [47]. Expression of CD177 mRNA is highly upregulated following endotoxin exposure. Overexpression of CD177 is a biomarker for thrombocythemia patients with elevated risk of thromboembolic complications [8]. While human CD177 contains nine exons that encode a protein with two LU domain repeats, mouse Cd177 is substantially larger with 17 exons that encode a larger protein with four LU domain repeats. Surprisingly, Cd177−/− mice displayed no discernible phenotype or any change in immune cells, other than decreased neutrophil counts in peripheral blood [47]. Absence of CD177 had no significant impact on CXCL1/KC- or fMLP-induced mouse neutrophil migration, but led to significant cell death [47].

Complement regulatory protein CD59

CD59 is an essential regulatory protein that protects hematopoietic and neuronal cells against complement-mediated osmolytic pore formation by binding C8 and/or C9 and inhibiting the incorporation of C9 into the membrane attack complex [17, 48–51]. CD2-mediated CD59 stimulation results in secretion of IL1A (IL-1α), IL6, and CSF2 (GM-CSF) in keratinocytes [52]. Inadequate complement regulation is associated with age-related macular degeneration [53]. Mutations in CD59 cause uncontrolled complement activation in hemolytic anemia, thrombosis, and cerebral infarction in paroxysmal nocturnal hemoglobinuria [54]. The mouse genome contains two homologs of CD59, termed Cd59a, and Cd59b. Mouse CD59B has approximately a sixfold higher specific activity than CD59A and is considered a true ortholog of human CD59. Cd59a deficiency exacerbated the skin disease and lymphoproliferative characteristic of the MRL/lpr murine lupus model suggesting that CD59A inhibits systemic autoimmunity in the MRL/lpr lupus model through a complement-independent mechanism [55]. Consistent with its higher specific activity, Cd59b−/− mice display a stronger phenotype including hemolytic anemia, anisopoikilocytosis, echinocytosis, schistocytosis, hemoglobinuria with hemosiderinuria, and platelet activation [56]. Cd59b−/− males suffer from progressive loss of fertility after 5 months of age [56].

Prostate stem cell antigen

Prostate stem cell antigen (PSCA) is a 123 amino acid protein with an N-terminal signal sequence, and a C-terminal GPI-anchoring sequence [57]. It was initially identified as a prostate-specific cell surface antigen in normal male tissues and found to be highly expressed in human prostate cancer [58, 59]. Later studies have revealed it to be more widely expressed. A genome-wide association study of Japanese patients with gastric cancer revealed that genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer [60]. Psca−/− mice are viable, and fertile, with similar rates of spontaneous or radiation-induced primary epithelial tumor formation as the wild-type mice. However, Psca−/− mice display an increased frequency of metastasis suggesting that PSCA may play a role in limiting tumor progression, and deletion of Psca promotes tumor migration and metastasis [61].

GPI-anchored high density lipoprotein-binding protein 1

GPI-anchored high density lipoprotein-binding protein 1 (GPIHBP1) is an endothelial cell protein expressed on the luminal face of capillaries in brown adipose tissue, heart, lung, and liver. GPIHBP1 binds high density lipoprotein and provides a platform for lipoprotein lipase (LPL)-mediated processing of chylomicron lipoprotein particles which transport dietary lipids from the intestines to other locations in the body. GPIHBP1 mutations that affect its ability to bind LPL or chylomicrons are associated with chylomicronemia [62–64]. Gpihbp1−/− mice cannot transport lipoprotein lipase to the capillary lumen, resulting in mislocalization of lipoprotein lipase within tissues, defective lipolysis of triglyceride-rich lipoproteins, and chylomicronemia [62–64]. Defective lipolysis causes reciprocal metabolic perturbations in Gpihbp1−/− mouse adipose tissue and liver. The essential fatty acid content of triglycerides is decreased and lipid biosynthetic gene expression is increased in adipose tissue, while the opposite changes occur in the liver [65].

Ly6/neurotoxin-1

As an allosteric modulator of nAChR function, Ly6/neurotoxin-1 (LYNX1) serves as a cholinergic brake that limits neuronal plasticity, balancing neuronal activity, and survival in the adult visual cortex [25, 66–68]. LYNX1 also inhibits SRC activation, suppressing mucin expression in the airway epithelium [69]. The LYNX1 gene is positioned in close proximity to SLURP2, leading to the mistaken idea that they are alternatively spliced isoforms of the same gene, a theory which was disproved recently [70]. LYNX1 is one of the genes that has shown accelerated evolution in humans relative to other primates, correlating with the increased brain size and complexity [71]. The juvenile brain exhibits high plasticity which is severely restricted in adulthood. Adult Lynx1−/− mice exhibited visual cortex plasticity similar to that of juveniles, suggesting that LYNX1 serves as a break for cortical plasticity [68]. Using the mouse model, it was demonstrated that LYNX1 plays a modulatory role in the aging brain, and that soluble LYNX1 may be useful for adjusting cholinergic-dependent plasticity and learning mechanisms [72–74].

Secreted Ly6/urokinase-type plasminogen activator receptor-related protein 1

Secreted Ly6/urokinase-type plasminogen activator receptor-related protein 1 (SLURP1) is expressed in a variety of cells including immune cells [75], sensory neurons [76], and epithelial cells [77–80], and secreted into plasma, saliva, sweat, urine, and tears [22, 81]. SLURP1 is downregulated in corneal neovascularization [82], asthmatic lungs [83], Barrett’s esophagus [84, 85], malignant melanomas [86], and squamous cell carcinomas [87, 88]. Mutations or deletions in SLURP1 cause autosomal recessive palmoplantar hyperkeratotic disorder ‘mal de Meleda’ [78, 81, 89–93]. SLURP1 is structurally similar to the snake and frog cytotoxin α-bungarotoxin, and acts as a CHRNA7 (α7nAChR)-ligand, regulating keratinocytes through cholinergic pathways [78, 94]. It modulates signal transduction, activation of the immune response, and cell adhesion, and blocks malignant transformation [75, 79, 95–97]. SLURP1 is proposed to modulate acetylcholine signaling through CHRNA7 [98]. We have documented that SLURP1 serves as an important immunomodulatory molecule at the ocular surface by acting as a soluble scavenger of urokinase (PLAU) [20–22]. Slurp1−/− mice develop signs of palmoplantar keratoderma including elevated keratinocyte proliferation, accumulation of lipid droplets in the stratum corneum, and defective epidermal barrier function reminiscent of mal de Meleda. Slurp1−/− mice also display decreased adiposity, low plasma lipid levels, and a neuromuscular abnormality (hind-limb clasping), suggesting additional functions for SLURP1 [99].

Secreted Ly6/urokinase-type plasminogen activator receptor-related protein 2 (SLURP2)

SLURP2 is expressed by human epidermal and oral keratinocytes, from where it is secreted into sweat and saliva, respectively [100]. SLURP2 expression is strongly induced in psoriatic skin lesions possibly by IL22, and is blocked by IFNG [70, 101]. SLURP2 blocks the effect of acetylcholine by binding CHRNA3 (α3nAChR), and delays keratinocyte differentiation and prevents apoptosis [100]. Although the SLURP2 and LYNX1 genes are closely linked leading to a mistaken idea that they are isoforms, it is now clear that they constitute separate transcription units that are differently regulated [70]. Slurp2−/− mice also develop signs of palmoplantar keratoderma and neuromuscular abnormality (hind-limb clasping) reminiscent of those seen in Slurp1−/− mice [99, 102].

Ly6/Plaur domain containing 1

Ly6/Plaur domain containing 1 (LYPD1), also known as LYNX2, is a prototoxin gene that is expressed in postmitotic central and peripheral neurons including subpopulations of motor neurons, sensory neurons, interneurons, and neurons of the autonomous nervous system [103]. LYPD1 is expressed at high levels in anxiety associated brain areas and plays an important role in regulating anxiety by binding and modulating neuronal nicotinic receptors [104, 105]. Ablation of Lypd1 alters the actions of nicotine on glutamatergic signaling in the prefrontal cortex, resulting in elevated anxiety-like behaviors [104].

Evolution of Ly6/uPAR family proteins

Ly6/uPAR family genes are conserved across species suggesting that they are evolutionarily ancient. Organization of the genes in this family in clusters on multiple chromosomes suggests that both gene duplications and translocations have played a role in their evolution. Comparison of the mouse and human Ly6/uPAR family genes reveals that while there are many orthologs, some Ly6 genes are only present in the mouse. The Ly6 gene complexes on human chromosomes 8, 19, 11, and 6 are syntenic with their counterparts on mouse Chromosomes 15, 7, 9, and 17, respectively, suggesting that these gene complexes were already present in their common ancestor. There are no human orthologs for the subcluster of murine Ly6 genes Ly6i, Ly6a, Ly6c1, Ly6c2, Ly6a2, Ly6g, Ly6g2, and Ly6f on Chromosome 15, and Pate10, Pate7, Pate6, Pate5, Pate12, Pate11, Pate9, Pate8, and Pate14 on Chromosome 9, suggesting that these regions may have arisen in the mouse through gene duplication after evolutionary divergence of these two species. What their functions are in the murine neutrophils and epididymis, respectively, where they are abundantly expressed, and how they are compensated in the corresponding human tissues, remains to be determined.

In order to evaluate the evolutionary relatedness of LU family proteins, we generated a phylogram by multiple sequence alignment of their amino acid sequences using web-based Clustal-Omega software, and visualized it with web-based software from Interactive Tree of Life (Fig. 2) [106–108]. Where multiple isoforms exist, we only used the sequence of the longest isoform. Analysis of the phylogenetic relationship among human and mouse Ly6/uPAR family proteins revealed that (i) human LY6K and mouse GML2 are the most ancestral Ly6 proteins with the longest unbranched streak in these two species, (ii) human and mouse LYPD6 are the most recent addition to the family closely followed by mouse LY6C1 and LY6C2, (iii) most of the secreted family proteins (with the notable exception of SLURP1 and SLURP2) form a separate cluster distinct from the GPI-anchored proteins, and (iv) several mouse PATE proteins (PATE4, 5, 6, 7, 8, 9, 10, 13, and 14) have long unbranched streaks suggesting that they have ancient origin and that the important function(s) that they serve have not changed much (Fig. 2).

Fig. 2.

Fig. 2

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Phylogram revealing the evolutionary relationship among mouse (ms-) and human (hu-) Ly6/uPAR family proteins. The phylogram was generated using the amino acid sequences in Clustal-Omega web-based program [106, 107] (http://www.ebi.ac.uk/Tools/msa/clustalo/). The display was generated using the methods described [108]. The length of each branch from the most recent branch point indicates the evolutionary distance, or the relative period of time the protein has been in its current state. Known GPI-anchored Ly6/uPAR family proteins are shown in red, and those secreted (without GPI-anchor) are shown in green. Those predicted to contain a GPI-anchor (but not yet experimentally proven) are in purple, and those predicted to not contain a GPI-anchor sequence (but not yet experimentally proven) are in black. Novel genes named in this study are indicated with an asterisk (*)

Concluding remarks

In this gene family update, we have summarized the current literature on the organization, expression patterns, functions, and evolution of human and mouse Ly6/uPLAR family genes. In addition, we identified and named many novel Ly6/uPAR family members. Considering that Ly6/uPLAR family members play critical roles in regulating immunological and physiological responses to infections and varying environmental conditions, it is imperative that we understand them in greater detail. Their involvement in regulating a wide range of functions such as progression of inflammation, complement activity, neuronal activity, angiogenesis, wound healing, and cancer growth indicates that Ly6/uPAR family members will be useful therapeutic targets. Additional insight into (i) the biological functions of individual family proteins, (ii) signaling cascades that regulate their expression and functions, and (iii) the identity of their interacting partners is expected to herald new modalities for diagnosis and treatment of diverse diseases.

Acknowledgements

Work in the Swamynathan lab was supported by R01EY022898 grant from the National Eye Institute (NEI), National Institutes of Health (NIH) (SKS), NEI Core Grant P30 EY08098, unrestricted grants from Research to Prevent Blindness, the Eye and Ear Foundation of Pittsburgh and the PA Lions Eye Research Sight Conservation Foundation (SKS), and “Fight for Sight/The Eye Bank for Sight” (EED). EAB is supported by NIH Grant U41HG003345 and Wellcome Trust grant 099129/Z/12/Z. MSM is supported by program project grant HG000330 from the National Human Genome Research Institute (NHGRI), NIH.

Footnotes

Competing interests

C.L. Loughner, None; E. A. Bruford, None; M.S. McAndrews, None; E.E. Delp, None; S. Swamynathan (Patent); S.K. Swamynathan, (Patent).

Authors’ contributions

CLL, EAB, MSM, EED, SS, and SKS were involved in drafting the manuscript and revising it critically for important intellectual content. Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content. All authors read and approved the final manuscript. Each author has agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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