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. 2016 Jul 16;22:797–815.

Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases

Inayat Ullah 1, Firoz Kabir 2, Muhammad Iqbal 1, Clare Brooks S Gottsch 2, Muhammad Asif Naeem 1, Muhammad Zaman Assir 3,4, Shaheen N Khan 1, Javed Akram 3,4, Sheikh Riazuddin 1,3,4, Radha Ayyagari 5, J Fielding Hejtmancik 6, S Amer Riazuddin 2,✉
PMCID: PMC4947966  PMID: 27440997

Abstract

Purpose

To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases.

Methods

Seven large familial cases with multiple individuals diagnosed with retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon–intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect.

Results

The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10−6) that affected individuals inherited the causal mutation from a common ancestor.

Conclusions

Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families.

Introduction

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of hereditary retinal disorders that primarily affect the ocular retina, with a prevalence of 1:4,000 [1,2]. RP is characterized by progressive degeneration of rod photoreceptors, leading to night blindness and constriction of the visual field, followed by the degeneration of cone photoreceptors, resulting in a total loss of vision [3]. The clinical manifestation of the disease includes pigmentary deposits in the retina, waxy disc pallor, and attenuation of retinal blood vessels [3]. Affected individuals often have severely abnormal or undetectable electroretinography responses, even in the early stage of the disease [3].

RP is a genetically heterogeneous disorder that manifests as an autosomal dominant, autosomal recessive, or X-linked trait. To date, a total of 73 genes have been implicated in the pathogenesis of RP. Of these, 27 genes have been associated with autosomal dominant RP (adRP) [4-30], while mutations in 50 genes have been identified in patients with autosomal recessive RP (arRP) [31-77]. Mutations in RHO (Gene ID: 6010; OMIM: 180380), RP1 (Gene ID: 6101; OMIM: 603937), NRL (Gene ID: 4901; OMIM: 162080), RPE65 (Gene ID: 6121; OMIM: 180069), BEST1 (Gene ID: 7439; OMIM: 607854), NR2E3 (Gene ID: 10,002; OMIM: 604485), and IMPDH1 (Gene ID: 3614; OMIM: 146690) have been identified in familial cases of adRP and arRP. Likewise, causal mutations in OFD1 (Gene ID: 8481; OMIM: 300170), RP2 (Gene ID: 6102; OMIM: 300757), and RPGR (Gene ID: 6103; OMIM: 312610) have been identified in RP cases with an X-linked inheritance pattern [78-80].

The tubby-like protein 1 (TULP1) gene consists of 15 coding exons spanning a 15 kb region and encodes for a 542 amino acid protein that has been associated with the transport of rhodopsin from its site of synthesis in the inner segments through the connecting cilium to the outer segments [81]. North and colleagues previously reported that TULP1 is expressed in many tissues, specifically in the rod and cone photoreceptor cells, and is involved in the transport of rhodopsin [82]. TULP1 has been associated with retinal degeneration, and pathogenic mutations in TULP1 have been identified in patients with arRP, rod-cone dystrophy, and Leber congenital amaurosis (LCA).

We previously reported five familial cases of arRP harboring mutations in TULP1 [83]. Since Iqbal et al. published their study, we have ascertained more than 200 familial cases of arRP. To investigate the genetic load of TULP1 in our familial cohort, we performed an exclusion linkage analysis that identified seven additional intermarried familial cases with multiple consanguineous marriages, diagnosed with early-onset RP. Clinical records available to us suggest an early, probably congenital onset, while exclusion analysis localized the retinal phenotype in all seven families to chromosome 6p harboring TULP1. Sanger sequencing of TULP1 identified causal mutations that segregated with the disease phenotype in the respective families and were absent in ethnically matched controls and genome-variant databases.

Methods

Clinical ascertainment

A total of more than 350 consanguineous Pakistani families with non-syndromic retinal dystrophies were recruited to identify new disease loci responsible for inherited visual diseases. The Institutional Review Boards (IRBs) of the National Centre of Excellence in Molecular Biology (Lahore, Pakistan), the National Eye Institute (Bethesda, MD), and Johns Hopkins University (Baltimore, MD) approved the study. All participating family members provided informed written consent that was endorsed by the respective IRBs and is consistent with the tenets of the Declaration of Helsinki.

A detailed clinical and medical history was obtained by interviewing the family members. Funduscopy was performed at the Layton Rehmatulla Benevolent Trust (LRBT) Hospital (Lahore, Pakistan). Electroretinography (ERG) measurements were recorded by using equipment manufactured by LKC (Gaithersburg, MD). Dark-adapted rod responses were determined through incident flash attenuated by −25 dB, whereas rod–cone responses were measured at 0 dB. The 30 Hz flicker responses were recorded at 0 dB to a background illumination of 17 to 34 cd/m2. All participating members voluntarily provided a sample of approximately 10 ml of blood that was stored in 50 ml Sterilin® falcon tubes containing 400 μl of 0.5 M EDTA. The blood samples were stored at −20 °C for long-term storage.

Genomic DNA extraction

Genomic DNA was extracted from white blood cells using a non-organic modified procedure as described previously [84]. The concentration of the extracted genomic DNA was estimated with a SmartSpec Plus Spectrophotometer (Bio-Rad, Hercules, CA).

Exclusion and linkage analysis

PCR was performed in a 5 μl mixture containing 40 ng of genomic DNA, 0.5 μl of 10 μM fluorescent-labeled primer pairs, 0.5 μl of 10X PCR Buffer (100 mM Tris HCl (pH 8.4), 400 mM NaCl, 15 mM MgCl2, 2.5 mM spermidine), 2 mM dNTP mix, and 0.2 U Taq DNA Polymerase (New England BioLabs Inc., Ipswich, MA). Initial denaturation was performed for 5 min at 95 °C, followed by ten cycles of 15 s at 94 °C, 15 s at 55 °C, and 30 s at 72 °C and then 20 cycles of 15 s at 89 °C, 15 s at 55 °C, and 30 s at 72 °C. The final extension was performed for 10 min at 72 °C. PCR products were mixed with a loading cocktail containing HD-400 size standards (Applied Biosystems, Foster City, CA) and resolved in an ABI PRISM 3100 Genetic Analyzer. Genotypes were assigned using Gene Mapper software from Applied Biosystems.

Linkage analysis was performed with alleles obtained through exclusion analysis using the FASTLINK version of MLINK from the LINKAGE Program Package [85,86]. Maximum LOD scores were calculated using ILINK from the LINKAGE Program Package. Autosomal recessive RP was investigated as a fully penetrant disorder with an affected allele frequency of 0.001. The marker order and distances between the markers were obtained from the National Center for Biotechnology Information chromosome 6 sequence maps.

Mutation screening

Individual exons of TULP1 were amplified with PCR using primer pairs designed by the primer3 program (Appendix 1). PCR reactions were completed in 10 μl volumes containing 20 ng of genomic DNA, 1 μl of the forward and reverse primers at 10 µM, 1 μl of 10X PCR Buffer (100 mM Tris HCl (pH 8.4), 400 mM NaCl, 15 mM MgCl2, 2.5 mM spermidine), 2 mM dNTP mix, 500 mM betaine, and 0.2 U Taq DNA Polymerase. PCR amplification consisted of a denaturation step at 95 °C for 5 min followed by a two-step touchdown procedure. The first step of ten cycles consisted of denaturation at 95 °C for 30 s, followed by a primer set-specific annealing for 30 s (annealing temperature decreased by 1 °C per cycle) and elongation at 72 °C for 45 s. The second step of 30 cycles consisted of denaturation at 95 °C for 30 s, followed by annealing (10 °C below the annealing temperature used in the first step) for 30 s and elongation at 72 °C for 45 s, followed by a final elongation at 72 °C for 5 min.

The PCR primers for each amplicon were used for bidirectional sequencing using the BigDye Terminator Ready Reaction mix according to the manufacturer’s instructions. The sequencing products were resolved on an ABI PRISM 3100 Genetic Analyzer (Applied Biosystems), and results were analyzed with Applied Biosystems SeqScape software.

In silico analysis

The degree of evolutionary conservation of c.1495+4A>C in other TULP1 orthologs was examined using the UCSC Genome browser. The effect of the c.1495+4A>C mutation on TULP1 mRNA splicing was predicted with an online bioinformatics tool, Human Splicing Finder 3.0 (HSF3). The possible impact of an amino acid change in the structure of TULP1 was examined with the SIFT and PolyPhen-2 tools available online.

Estimating the likelihood of a common founder effect

A total of five single nucleotide polymorphisms (SNPs) within 11 kb of TULP1 were selected, and one affected individual from each family was genotyped to construct the causal haplotype. SNP genotypes of 96 individuals of Pakistani descent were obtained from the 1000 Genomes database and used to construct ethnically matched control haplotypes. The haplotype frequencies were estimated to calculate the likelihood of a common founder effect.

Results

We ascertained a large cohort of highly intermarried familial cases of retinal dystrophies to investigate the genetic basis of arRP. We previously reported five familial cases of arRP harboring pathogenic mutations in TULP1 [83]. Since Iqbal and colleagues [83] published their study, we have ascertained more than 200 additional familial cases of arRP, and therefore, we reexamined our expanded cohort for mutations in TULP1 with closely spaced fluorescently labeled short tandem repeat (STR) markers spanning the TULP1 locus. These analyses identified seven additional intermarried families (PKRP259, PKRP268, PKRP301, PKRP309, PKRP356, PKRP364, and PKRP367) linked to TULP1 (Figure 1).

Figure 1.

Figure 1

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Pedigree drawings with haplotype formed from alleles of chromosome 6p microsatellite markers. A: PKRP259. B: PKRP268. C: PKRP301. D: PKRP309. E: PKRP356. F: PKRP364. G: PKRP367. The alleles forming the risk haplotype are shaded black, and the alleles that do not cosegregate with retinitis pigmentosa (RP) are shown in white. Squares = males; circles = females; filled symbols = affected individuals; double line between individuals = consanguineous marriage; diagonal line through a symbol = deceased family member.

Affected individuals in these families fulfilled the diagnostic criteria of RP (Table 1). Fundus photographs of affected individuals revealed typical symptoms of RP, including attenuated retinal arteries, a waxy, pale optic disc, and bone spicule–like pigment deposits in the lateral and mid-periphery of the retina (Figure 2). Likewise, scotopic ERG recordings measured at −25 dB and photopic responses at 0 dB (30 Hz flicker) were undetectable in affected individuals, suggestive of compromised rod and cone photoreceptor cells, while unaffected individuals exhibited rod and cone responses in the normal range (Figure 3).

Table 1. Clinical characteristics of the patients screened for TULP1 mutations.

Family ID C-Age (Yr.) D-age
(Yr.) First symptoms Night blindness Fundus examination Electroretinography
 Visual acuity
OD OS OD OS
PKRP259
 10
 28
 6
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/36
 6/40
PKRP259
 15
 22
 7
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/24
 6/24
PKRP268
 12
 17
 7
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/20
 6/20
PKRP268
 13
 14
 6
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/20
 6/20
PKRP301
 14
 20
 5
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/18
 6/20
PKRP301
 17
 14
 5
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/20
 6/24
PKRP309
 11
 34
 6
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/30
 6/28
PKRP309
 15
 25
 7
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/25
 6/25
PKRP356
 10
 10
 5
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/12
 6/12
PKRP356
 12
 8
 5
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/20
 6/20
PKRP364
 10
 58
 7
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/50
 6/50
PKRP364
 20
 21
 8
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/24
 6/24
PKRP367
 11
 31
 6
 Night blindness
 progressive
 MD, Art. Atten, Pig.dep, PD
 NAB, NF
 NAB, NF
 6/24
 6/28
PKRP367 12 20 7 Night blindness progressive MD, Art. Atten, Pig.dep, PD NAB, NF NAB, NF 6/20 6/20
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MD: macular degeneration; Art. Atten: artery attenuation; Pig.dep: pigment deposit; PD: Pale optic disc; NAB: no ‘a’ or ‘b’ wave response; NF: no flicker response; C-Age: current age; D-Age: age at first diagnosis of the retinal dystrophy.

Figure 2.

Figure 2

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Fundus photographs of affected individuals illustrating symptoms of retinitis pigmentosa. A: OD and OS of individual 10 (affected: 30 years) of family PKRP259. B: OD and OS of individual 11 (affected: 18 years) of family PKRP309. C: OD and OS of individual 8 (unaffected: 52 years) of family PKRP259. Fundus photographs of affected individuals show bone spicule-like pigmentation in the mid-periphery of the retina, attenuated retinal arterioles, severe maculopathy, and disc pallor. OD = oculus dexter; OS = oculus sinister.

Figure 3.

Figure 3

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Electroretinography responses of PKRP259 family members. In the stimulus conditions, scotopic 0 dB bright flashes elicit rod responses (left column of each pair), and a photopic 0 dB, 30 Hz flicker elicits cone responses (right column of each pair). Responses are of A) OD and B) OS of individual 10 (affected: 30 years); C) OD and D) OS of individual 14 (affected: 25 years); and E) OD and F) OS of individual 8 (unaffected: 52 years). The affected individuals exhibit undetectable electroretinography responses whereas the unaffected individual exhibits normal a- and b-waves suggestive of normal rod and cone function. OD = oculus dexter; OS = oculus sinister.

All seven families yielded positive two-point LOD scores for chromosome 6p markers flanking TULP1 (Table 2). We sequenced all coding exons and the exon–intron boundaries of TULP1, which identified four different causal mutations. They included a novel missense variation in exon 15, c.1561C>T (p.P521S), in PKRP259 (Figure 4A); a homozygous splice site variant in intron 14, c.1495+4A>C, in PKRP268 that affects the conserved splice donor site (Figure 4B); a single base pair substitution in exon 14, c.1466A>G (p.K489R), in four families, PKRP301 (Figure 4C), PKRP309 (Figure 4D), PKRP356 (Figure 4E), and PKRP367 (Figure 4G); and a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*), in PKRP364 (Figure 4F). These variants segregated in their respective families: Affected individuals were homozygous whereas unaffected individuals were heterozygous carriers or homozygous for the wild-type allele. These mutations were absent in ethnically matched control chromosomes and were not present in the 1000 Genomes database.

Table 2. Two-point LOD scores of chromosome 6p markers for families A) PKRP259, B) PKRP268, C) PKRP301, D) PKRP309, E) PKRP356, F) PKRP364, and G) PKRP367.

Markers
 cM
 Mb
 0.00
 0.01
 0.05
 0.09
 0.10
 0.20
 0.30
 Zmax
 θmax
A
D6S439
 48.26
 35.18
 2.21
 2.16
 1.95
 1.74
 1.68
 1.15
 0.65
 2.21
 0.00
D6S1611
 47.71
 35.40
 2.79
 2.73
 2.50
 2.26
 2.20
 1.57
 0.93
 2.79
 0.00
D6S1645 48.26 35.61 2.02 1.97 1.77 1.57 1.51 1.00 0.51 2.02 0.00
B
D6S439
 48.26
 35.18
 2.30
 2.26
 2.06
 1.86
 1.80
 1.27
 0.72
 2.30
 0.00
D6S1611
 47.71
 35.40
 2.48
 2.43
 2.22
 2.00
 1.94
 1.39
 0.85
 2.48
 0.00
D6S1645 48.26 35.61 3.33 3.26 2.99 2.72 2.65 1.94 1.22 3.33 0.00
C
D6S439
 48.26
 35.18
 -∞
 −5.70
 −3.82
 −2.96
 −2.40
 −2.00
 −1.83
 −2.00
 0.20
D6S1611
 47.71
 35.40
 1.14
 1.12
 1.07
 1.02
 0.97
 0.93
 0.90
 1.14
 0.00
D6S1645 48.26 35.61 1.44 1.40 1.33 1.25 1.18 1.11 1.07 1.44 0.00
D
D6S439
 48.26
 35.18
 1.55
 1.52
 1.46
 1.39
 1.33
 1.27
 1.23
 1.55
 0.00
D6S1611
 47.71
 35.40
 1.58
 1.55
 1.48
 1.42
 1.35
 1.28
 1.25
 1.58
 0.00
D6S1645 48.26 35.61 0.66 0.64 0.61 0.58 0.55 0.52 0.50 0.66 0.00
E
D6S439
 48.26
 35.18
 2.19
 2.15
 2.06
 1.98
 1.89
 1.80
 1.76
 2.19
 0.00
D6S1611
 47.71
 35.40
 0.49
 0.47
 0.44
 0.41
 0.38
 0.35
 0.33
 0.49
 0.00
D6S1645 48.26 35.61 2.19 2.15 2.06 1.98 1.89 1.80 1.76 2.19 0.00
F
D6S439
 48.26
 35.18
 -∞
 −0.81
 0.01
 0.33
 0.50
 0.59
 0.62
 0.62
 0.30
D6S1611
 47.71
 35.40
 2.03
 1.98
 1.89
 1.79
 1.69
 1.59
 1.54
 2.03
 0.00
D6S1645 48.26 35.61 3.93 3.86 3.71 3.56 3.41 3.25 3.17 3.93 0.00
G
D6S439
 48.26
 35.18
 0.73
 0.71
 0.64
 0.45
 0.10
 0.20
 0.30
 0.73
 0.00
D6S1611
 47.71
 35.40
 0.43
 0.42
 0.37
 0.46
 0.55
 0.37
 0.19
 0.43
 0.00
D6S1645 48.26 35.61 0.43 0.42 0.37 0.46 0.32 0.20 0.10 0.43 0.00
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Figure 4.

Figure 4

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Sequence chromatograms of TULP1 variations identified in this study. A: Unaffected individual 8 is a heterozygous carrier, and affected individual 10 is homozygous for the single base pair substitution c.1561C>T in family PKRP259. B: Unaffected individual 19 is a heterozygous carrier, and affected individual 12 is homozygous for the splice region variant c.1495+4A>C in family PKRP268. C: Unaffected individual 12 is a heterozygous carrier, and affected individual 17 is homozygous for the single base pair substitution c.1466A>G in family PKRP301. D: Unaffected individual 7 is a heterozygous carrier, and affected individual 15 is homozygous for the single base pair substitution c.1466A>G in family PKRP309. E: Unaffected individual 8 is a heterozygous carrier, and affected individual 10 is homozygous for the single base pair substitution c.1466A>G in family PKRP356. F: Unaffected individual 18 is a heterozygous carrier, and affected individual 10 is homozygous for the two-base deletion c.286_287delGA in family PKRP364. G: Unaffected individual 9 is a heterozygous carrier, and affected individual 12 is homozygous for the single base pair substitution c.1466A>G in family PKRP367.

We examined the evolutionary conservation of amino acid Pro521 and nucleotide c.1495+4A and found that Pro521 and c.1495+4A are completely conserved in TULP1 orthologs (Figure 5). We examined the possible impact of the Pro521Ser substitution on the TULP1 protein using the PolyPhen-2 algorithm, which suggested that the serine substitution at position 521 would probably be damaging. Subsequently, we evaluated the effect of the c.1495+4A>C variation on TULP1 mRNA splicing using Human Splice Finder 3 (HSF3). HSF3 generated consensus values of 82.12 and 73.32 for the wild-type (c.1495+4A) and mutant (c.1495+4C) nucleotides, respectively (Figure 6A,B). The predicted consensus value deviation of −10.72 for c.1495+4A>C suggests that the wild-type splice donor site will be broken. Loss of the wild-type splice site will result in the retention of intron 14 of TULP1 (Figure 6B), resulting in a frame shift and is likely to produce aberrant TULP1 (p.P499Rfs104*).

Figure 5.

Figure 5

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Sequence conservation of amino acid Pro521 and nucleotide 1495+4A in TULP1 orthologs. Primates are green, placental mammals are blue, and vertebrates are purple. The arrow points to amino acid residue Pro521 and nucleotide 1495+4A, which were mutated in individuals with retinitis pigmentosa.

Figure 6.

Figure 6

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In silico analysis of the splice donor site mutation in TULP1. The HSF3 algorithm predicted a consensus value (CV) of A) 82.12 for the wild-type (c.1495+4A) and B) 73.32 (c.1495+4C) for the mutant splice donor site. The CV deviation of −10.72 suggests that the loss of the wild-type splice site will result in the retention of intron 14 of TULP1, resulting in a frame shift likely to produce aberrant TULP1 (p.P499Rfs104*).

All four families (PKRP301, PKRP309, PKRP356, and PKRP367) harboring the K489R allele were recruited from the Punjab province of Pakistan; they reside in different cities with no known relationship between them. We previously reported four families (PKRP084, PKRP111, PKRP122, and PKRP171) harboring the same missense variation, and SNP analysis suggested a common ancestor who transmitted the causal allele [83]. The presence of a common causal mutation in eight familial cases of our cohort prompted us to investigate the ancestral relationships among the cases. We used single nucleotide polymorphisms in the immediate neighborhood of the causal mutation, which identified a haplotype (CTGT/CC) common to all four families harboring the K489R allele (Table 3) suggestive of a common founder effect. To confirm the effect, we retrieved the genotype information of ethnically matched controls from the 1000 Genomes database and estimated the respective population haplotype frequencies (four of the five SNPs, including rs12665445, rs7770128, rs12215920, and rs7764472, were to construct the haplotype). The CTGC haplotype had an allele frequency of 0.04 in the Punjabi population of Pakistani decent, which suggested a high probability (p>2.56×10−6) that affected individuals in these four families inherited the causal mutation from a common ancestor. Interestingly, these odds increased significantly (p>6.5×10−12) when PKRP084, PKRP111, PKRP122, and PKRP171 (harboring the K489R allele reported by Iqbal et al. [83]) were included in the analysis.

Table 3. Single nucleotide polymorphism (SNP) haplotypes of affected individuals in PKRP301, PKRP309, PKRP356, and PKRP367 harboring the c.1466A>G (p.K489R) mutation in TULP1.

Family Individual c.1466A>G
 rs12665445
 rs7770128
 rs12215920
 rs34126023
 rs7764472
Chr6: 35500039 Chr6: 35500262 Chr6: 35505901 Chr6: 35506296 Chr6: 35509796 Chr6: 35511797
PKRP301
 14
 G
 C
 T
 G
 T/C
 C
PKRP309
 15
 G
 C
 T
 G
 T/C
 C
PKRP356
 10
 G
 C
 T
 G
 T/C
 C
PKRP367 12 G C T G T/C C
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Discussion

Here, we report seven consanguineous families recruited from the Punjab province of Pakistan with multiple members manifesting cardinal symptoms of RP. Exclusion analysis with closely spaced STR markers localized the linkage interval in all seven families to chromosome 6p21.3 harboring TULP1, while bidirectional Sanger sequencing of TULP1 identified a novel missense variation, a splice site variant, a previously reported single base pair substitution, and a two-base deletion. All these variants segregate with the disease phenotype in the respective families. These variations were absent in 190 ethnically matched control chromosomes, and the absence of the variants in the 1000 Genomes database, the NHLBI Exome Variant Server, and the dbSNP database strongly suggests that these variations are responsible for the retinal phenotype of the patients reported in this study.

As shown in Table 4, a total of 50 causal mutations have been reported in TULP1, and mutations in TULP1 account for 1–2% of arRP cases in different ethnic populations worldwide [37,81,83,87-116]. Previously, Gu and colleagues screened a large cohort of patients of German origin with arRP and identified the K489R pathogenic allele in TULP1 [92]. More recently, Maria and colleagues identified the K489R allele in a family of Pakistani descent [113]. We found the same residue, p.K489R, in eight families; therefore, this allele is by far the most abundant RP-associated allele of TULP1 found in the Pakistani population. In our large cohort of more than 350 familial cases of arRP, we identified 12 families harboring causal mutations in TULP1; however, as eight of these families harbor a common ancestral mutation, we estimate that TULP1 contributes nearly 1% of the total genetic load of arRP in our cohort.

Table 4. List of mutations reported in TULP1-associated retinal dystrophies.

Exon/ Intron Nucleotide change Amino acid change Phenotype Reference
Exon 1
 c.3G>A
 p.M1I
 arRP
 87
Intron 2
 c.99+1G>A
 Aberrant splicing
 LCA, arRP
 88, 89
Exon 4
 c.280G>T
 p.D94Y
 LCA
 90
Intron 4
 c.350–2delAGA, (IVS4–2delAGA)
 Aberrant splicing
 arRP
 91
Exon 5
 c.394_417del
 p.E120_D127del
 arRP
 92
Exon 5
 c.539G>A
 p.R180H
 LCA
 93
Exon 6
 c.627delC
 p.S210QfsX27
 LCA
 94
Exon 6
 c.629C>G
 p.S210*
 RP
 95
Intron 7
 c.718+2T>C
 Aberrant splicing
 JRP, LCA
 96
Exon 7
 c.725_728delCCAA
 p.P242Qfs×16
 LCA
 97
Exon 10
 c.901C>T
 p.Q301*
 LCA, RCD
 98, 99
Exon 10
 c.937delC
 p.Q301fs9*
 arRP
 91
Exon 10
 c.932G>A
 p.R311Q
 arRP
 100
Exon 10
 c.956G>A
 p.G319D
 RP
 101
Exon 10
 c.961T>G
 p.Y321D
 LCA
 97
Intron 10
 c.999+5G>C
 Aberrant splicing
 JRP, LCA
 96
Exon 11
 c.1025G>A
 p.R342Q
 arRP
 100
Exon 11
 c.1047T>G
 p.N349K
 arRP
 102
Exon 11
 c.1064A>T
 p.D355V
 LCA
 97
Exon 11
 c.1087G>A
 p.G363R
 RCD
 103
Exon 11
 c.1081C>T
 p.R361*
 LCA
 104
Exon 11
 c.1102G>T
 p.G368W
 LCA
 89
Intron 11
 c.1112+2T>C (IVS11 ds T-C +2)
 Aberrant splicing
 arRP
 105
Intron 11
 c.1113–2A>C (IVS11 as A-C −2)
 Aberrant splicing
 LCA
 97
Exon 12
 c.1138A>G
 p.T380A
 LCA, arRP
 83, 106, 107
Exon 12
 c.1145T>C
 p.F382S
 arRP
 108
Exon 12
 c.1198C>T
 p.R400W
 arRP, LCA, RD
 89, 109, 110
Exon 12
 c.1199G>A
 p.A400Q
 arRP
 111
Exon 12
 c.1204G>T
 p.E402*
 LCA
 89
Intron 12
 c.1224+4A>G, (IVS12+4A>G)
 Aberrant splicing
 arRP
 92
Exon 13
 c.1246C>T
 p.R416C
 ArRP
 87
Exon 13
 c.1258C>A
 p.R420S
 RCD
 112
Exon 13
 c.1259G>C
 p.R420P
 arRP
 88
Exon 13
 c.1318C>T
 p.R440*
 LCA
 94
Exon 14
 c.1349G>A
 p.W450*
 LCA
 90
Exon 14
 c.1376T>A
 p.I459K
 arRP
 37, 88
Exon 14
 c.1376T>C
 p.I459T
 arRP
 105
Exon 14
 c.1376_1377delTA
 p.I459Rfs×12
 LCA
 97
Exon 14
 c.1381C>G
 p.L461V
 JRP, LCA
 96
Exon 14
 c.1444C>T
 p.R482W
 arRP
 81, 109
Exon 14
 c.1445G>A
 p.A482Q
 arRP
 107
Exon 14
 c.1466A>G
 p.K489R
 arRP
 83, 92, 113
Exon 14
 c.1472T>C
 p.F491L
 arRP
 88
Intron 14
 c.1495+1G>A, (IVS14+1G>A)
 Aberrant splicing
 arRP
 37
Intron 14
 c.1495+2_1495+3insT
 Aberrant splicing
 arRP
 114
Intron 14
 c.1496–6C>A, (IVS14–6C>A)
 Aberrant splicing
 arRP
 88, 92
Exon 15
 c.1511_1521delTGCAGTTCGGC
 p.L504fs140*
 arRP
 81
Exon 15
 c.1518C>A
 p.F506L
 LCA
 94
Exon 15
 c.1582_1587dupTTCGCC
 p.F528_A529dup
 LCA/arRP
 115
Exon 15 c.1604T>C p.F535S LCA 116
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arRP: autosomal recessive RP; RD: Retinal degeneration; LCA: Leber congenital amaurosis; JRP: Juvenile onset RP; RCD: Rod-Cone Dystrophy.

Identification of causal mutations reaffirmed the role of TULP1 in the pathogenesis of autosomal recessive RP and reiterates the heterogeneity associated with the disease phenotype. We compared the clinical phenotype of patients with arRP in PKRP084, PKRP111, PKRP122, and PKRP171 harboring the K489R allele reported by Iqbal et al. [83] with affected individuals in PKRP301, PKRP309, PKRP356, and PKRP367. However, we did not identify any distinction between the clinical phenotypes of affected individuals in these eight familial cases. All affected individuals in these familial cases manifested cardinal symptoms of RP, including attenuated retinal arteries and bone spicule–like pigment deposits accompanied by undetectable scotopic and photopic ERG responses. Identification of causal alleles responsible for arRP will help diagnostic efforts to identify carrier status in intermarried familial cases, and subsequent genetic counseling will help families make educated decisions regarding arranged marriages and screening for the status of newborns. In conclusion, we report seven familial cases harboring causal mutations in TULP1, including a common ancestral mutation that has now been identified in eight apparently unrelated familial cases.

Acknowledgments

We are thankful to all family members for their participation in this study. This study was supported in part by the Higher Education Commission, Islamabad, Pakistan (SR), and by the National Eye Institute Grant R01EY021237–01 (RA and SAR).

Appendix 1. Primer sequences for the amplification of TULP1.

To access the data, click or select the words “Appendix 1.”

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