TABLE 2.
Growth factors, receptors and related proteins implicated in syndromic hearing loss
| Gene | OMIM | Description; cellular location | Protein/alias | Function | Hearing loss type | Locus; mode of inheritance |
|---|---|---|---|---|---|---|
| ACVR1 | 102576 | ACtiVin a Receptor, type I; transmembrane | ACVR1/ ACVRLK2/ ALK2 | General role as receptor for Activin, BMP or TGFB mediated SMAD signaling | Variable age of onset, conductive or sensorineural, mild to severe | Fibrodysplasia ossificans progressiva; dominant |
| ADGRV1 | 602851 | ADhesion G protein-coupled Receptor V1; transmembrane | ADGRV1/ GPR98/ MASS1/ VLGR1/ KIAA0686 | Receptor function unknown, component of stereocilia ankle links | Sensorineural, bilateral, progressive, moderate to severe | Usher syndrome 2C; recessive |
| BMP2 | 617877 | Bone Morphogenetic Protein 2, secreted | BMP2/BMP2A | Endochondral ossification | External ear malformations, conductive | Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies; dominant |
| BMP2 | 617877 | Bone Morphogenetic Protein 2, secreted | BMP2/BMP2A | Endochondral ossification | Conductive | Otosclerosis |
| BMP4 | 112262 | Bone Morphogenetic Protein 4; secreted | BMP4/BMP2B/BMP2B1 | Specification of sensory and nonsensory regions of cochlea | Conductive | Otosclerosis |
| BMP4 | 112262 | Bone Morphogenetic Protein 4; secreted | BMP4/BMP2B/BMP2B1 | Specification of sensory and nonsensory regions of cochlea | Sensorineural, mild to moderate | Stickler syndrome and renal dysplasia; dominant |
| BMP7 | 112267 | Bone Morphogenetic Protein 7; secreted | BMP7/OP1 | Specifies tonotopic axis in developing inner ear | Sensorineural, bilateral, moderate | Ocular, brain, ear, palate, and skeletal anomalies; dominant |
| BRAF | 164757 | v-RAF murine sarcoma viral oncogene homologue B1; cytoplasmic, cell membrane, nuclear | BRAF/BRAF1/RAFB1 | Regulator of MAPK/ERK signaling pathway | Outer ear malformation, sensorineural | LEOPARD syndrome 3; dominant |
| DVL1 | 601365 | Dishevelled 1, cytoplasmic | DVL1/DVL | Functions downstream of WNT signaling | Outer ear malformation, conductive or sensorineural | Robinow syndrome, autosomal dominant 2; dominant |
| DVL3 | 601368 | Dishevelled 3, cytoplasmic | DVL3 | Functions downstream of WNT signaling | Rare ear malformation and hearing loss | Robinow syndrome, autosomal dominant 3; dominant |
| EDN3 | 131242 | Endothelin 3, secreted | EDN3/ET3 | Development of neural crest and its cell lineages | Sensorineural, Mild to profound, unilateral or bilateral | Waardenburg syndrome, type 4B, WS4B; dominant or recessive |
| EDNRA | 131243 | Endothelin Receptor, type A; transmembrane | EDNRA/ETA/ETRA | Development of neural crest and its cell lineages | Outer ear malformation, childhood onset, conductive, moderate | Mandibulofacial dysostosis with alopecia; dominant |
| EDNRB | 131244 | Endothelin Receptor, type B; transmembrane | EDNRB/ETB/ETBR | Development of neural crest and its cell lineages | Sensorineural, mild to profound, unilateral or bilateral | Waardenburg syndrome, type 4A, WS4A, WS1, WS2; dominant and recessive Waardenburg syndrome, type 2A, WS2A; dominant; ABCD syndrome; recessive |
| ESRRG | 602969 | EStrogen Related Receptor Gamma, nuclear | ESRRG/ERR3 | Unknown | Prelingual, sensorineural, bilateral, mild to moderate | Hearing loss with mild intellectual disability; recessive |
| FGF3 | 164950 | Fibroblast Growth Factor 3, secreted | FGF3/INT2 | Induction of inner ear fate | Outer and inner ear anomalies, prelingual, sensorineural, profound | Congenital deafness, inner ear agenesis, microtia, microdontia; recessive |
| FGF10 | 602115 | Fibroblast Growth Factor 10; secreted | FGF10 | Specification of nonsensory regions of inner ear | Outer ear malformation, conductive, sensorineural or mixed hearing loss | LADD syndrome; dominant |
| FGFR1 | 136350 | Fibroblast Growth Factor Receptor 1; transmembrane | FGFR1/FLT2/FLG | Early cell proliferation of cochlea, differentiation of sensory epithelium | Outer ear malformation in some, unilateral | Kallmann syndrome 2; dominant |
| FGFR2 | 176943 | Fibroblast Growth Factor Receptor 2; transmembrane | FGFR2/TK14 | Essential for inner ear morphogenesis | Outer ear malformations may be present, prelingual or postlingual, conductive or sensorineural or mixed, bilateral mild to severe | Apert syndrome, Crouzon syndrome CFD1; LADD syndrome; Saethre-Chotzen Syndrome, Pfeiffer syndrome type 3; Dominant |
| FGFR3 | 134934 | Fibroblast Growth Factor Receptor 3; transmembrane | FGFR3 | Controls fate of supporting cells in organ of Corti | Sensorineural or mixed, mild to moderate | CATSHL syndrome, LADD syndrome, Muenke syndrome, SADDAN; dominant or recessive |
| GDF6 | 601147 | Growth/Differentiation Factor 6; secreted | GDF6/CDMP2 | Growth of cartilage elements, SMAD signaling | Outer ear malformation, conductive or sensorineural, mild to moderate | Klippel-Feil syndrome 1; dominant multiple synostoses syndrome, dominant |
| GNAI3 | 139370 | Guanine Nucleotide-binding protein, Alpha-Inhibiting activity polypeptide 3; cytoplasmic | GNAI3/ G protein | Mediator of signaling involving G protein-coupled endothelin receptor | Outer ear malformation, conductive or sensorineural, mild to moderate | Auriculocondylar syndrome 1; dominant |
| GPRASP2 | 300969 | G Protein-coupled Receptor-Associated Sorting Protein 2; cytoplasmic | GPRASP2/GASP2 | Turnover of G-protein-Coupled Receptors | External ear malformations, congenital or progressive, bilateral, mixed hearing loss, moderate to profound | DFNX7, Deafness X-linked 7, recessive |
| GPSM2 | 609245 | G Protein Signaling Modulator 2; cytoplasmic | GPSM2/LGN/PINS | Asymmetric localization of kinocilia in postmitotic hair cells | Prelingual, sensorineural, bilateral, severe to profound | Chudley-McCullough Syndrome; recessive |
| IGF1 | 147440 | Insulin-like Growth Factor I; secreted | IGF1/IGFI/ Somatomedin C | Postnatal differentiation and maturation of cochlea and central auditory neurons | Sensorineural, prelingual, bilateral, profound | Insulin-like growth factor I deficiency; recessive |
| IGF1R | 147340 | Insulin-like Growth Factor I Receptor; transmembrane | IGF1R | Postnatal differentiation and maturation of cochlea and central auditory neurons | Bilateral, profound | Insulin-like growth factor I, resistance to; dominant |
| JAG1 | 601920 | JAGged 1; transmembrane | JAG1/JAGL1 | Patterning of the organ of Corti, outer hair cell number | Mild to severe, mixed, mid-frequency | Deafness, congenital heart defects, and posterior embryotoxon; dominant |
| KIT | 164920 | V-KIT Hardy-Zuckerman 4 feline sarcoma viral oncogene homologue; transmembrane | KIT/SCFR | Proliferation, migration from the neural crest, differentiation of melanoblasts | Prelingual, sensorineural, profound | Piebaldism (Woolf’s syndrome); dominant |
| KITLG | 184745 | KIT Ligand; trasmembrane and secreted | KITLG/KL/KITL/MGF/SCF/SF | Proliferation, migration from the neural crest, differentiation of melanoblasts | Congenital, stable unilateral and asymmetric hearing loss | Waardenburg syndrome, type 2; dominant |
| LRP2 | 600073 | Low density lipoprotein Receptor-related Protein 2; transmembrane | LRP2/ Glycoprotein 330/ megalin | Endocytic receptor, Development of ear | Outer ear malformation, sensorineural, severe to profound | Donnai-Barrow syndrome; recessive |
| LRP4 | 604270 | Low density lipoprotein Receptor-related Protein 4; transmembrane | LRP4/MEGF7 | Causes narrowing of foramina of the cranial nerves which leads to hearing loss | Hearing loss present, but no details provided | Sclerosteosis 2, recessive |
| LRP5 | 603506 | Low density lipoprotein Receptor-related Protein 5; transmembrane | LRP5/LRP7/LR3 | Co-receptor during WNT signaling | Sensorineural, | Osteosclerosis, dominant |
| MAP3K7 | 602614 | Mitogen-Activated Protein Kinase kinase kinase 7; cytoplasmic | MAP3K7/ TAK1 | Mediator of TGFB and BMP signaling | Outer and inner ear malformations, conductive. bilateral | Cardiospondylocarpofacial syndrome; dominant |
| MET | 164860 | Mesenchymal EpithelialTransition factor; transmembrane | MET/HGFR | Incorporation of neural crest cells into the stria vascularis | Prelingual, sensorineural, bilateral, severe to profound | Deafness with arthrogryposis and distinctive facial features; recessive |
| NDP | 300658 | Norrin cystine knot growth factor; secreted | NDP/Norrin | Vascularization of cochlea with particular importance in stria vascularis and spiral ganglion, binds to Frizzled receptors | Sensorineural, postlingual, childhood or adult onset, bilateral, progressive, mild to profound | Norrie Disease; X-linked recessive |
| NLRP3 | 606416 | NLR family, Pyrin domain-containing 3; cytoplasmic | NLRP3/CIAS1/NALP3/PYPAF1/Cryopyrin | Leads to events which end in production of cytokine IL-1β | Postlingual, sensorineural, bilateral, progressive, severe | CINCA syndrome, Muckle-Wells syndrome; dominant |
| NOG | 602991 | NOGgin, mouse homologue of; secreted | NOG | Inhibits signaling by GDF6, BMP, and TGFB | Stapes ankylosis, conductive, rarely sensorineural, progressive | Multiple synostoses syndrome 1; dominant |
| NOTCH2 | 600275 | Drosophila homolog of Notch, 2; transmembrane | NOTCH2 | Patterning of the organ of Corti | Childhood onset, conductive, rarely sensorineural, mild to moderate | Hajdu-Cheney syndrome; dominant |
| NOTCH3 | 600276 | Drosophila homolog of Notch, 3; transmembrane | NOTCH3 | Patterning of the organ of Corti | Outer ear malformation, conductive or mixed, bilateral, moderate | Lateral meningocele syndrome; dominant |
| NSD1 | 606681 | Nuclear receptor-binding Su-var, enhancer of zeste, and trithorax Domain protein 1; nuclear | NSD1/ARA267 | unknown | Childhood onset, otitis media, conductive | Sotos syndrome 1; dominant |
| PTPN11 | 176876 | Protein-Tyrosine Phosphatase, Nonreceptor-type, 11; cytoplasmic | PTPN11/PTP2C/SHP2 | Mediates signaling by HGF, EGF through activation of RAS/MAPK pathways | Outer ear malformation, Childhood or adult onset, sensorineural or mixed, unilateral or bilateral, mild to profound | Noonan syndrome 1, LEOPARD syndrome 1; dominant |
| RAF1 | 164760 | v-Raf-1 Rapidly Accelerated Fibrosarcoma murine leukemia viral oncogene homologue 1, cytoplasmic | RAF1/CRAF | Secondary signal transducer for receptor tyrosine kinase via RAS/MAPK pathways | Outer ear malformation, childhood or adult onset,sensorineural or mixed, unilateral or bilateral, mild to profound | Noonan Syndrome 5, LEOPARD syndrome 2; dominant |
| ROBO1 | 602430 | Roundabout, drosophila, homolog of 1; transmembrane | ROBO1/SAX3 | Axon guidance receptor | Sensorineural, profound | combined pituitary hormone deficiency; recessive |
| SEMA3E | 608166 | SEMAphorin 3E; secreted | SEMA3E/SEMAH/ KIAA0331 | Cell migration, neural crest and otic placode induction | Outer and inner ear malformations, prelingual, mixed or sensorineural, progressive, severe or profound | CHARGE syndrome; dominant |
| SLITRK6 | 609681 | SLIT- and NTRK-like family, member 6; transmembrane | SLITRK6 | Survival and innervation of sensory neurons | Sensorineural or auditory neuropathy spectrum syndrome, prelingual, bilateral moderate to profound | Deafness and myopia; recessive |
| SMAD4 | 600993 | Mothers Against Decapentaplegic, drosophila, homolog of, 4; cytoplasmic | SMAD4/MADH4/DPC4 | Mediator of signaling of BMP and TGFB superfamily members | Outer ear malformations, early onset, mixed | Myhre syndrome; dominant |
| TBL1X | 300196 | Transducin-Beta-Like 1, X-linked | TBL1X/TBL1/EBI | Component of the nuclear corepressor (NCOR) complex | Mild hearing loss | X-linked |
| TBL1Y | 400033 | Transducin-Beta-Like 1, Y-linked | TBL1Y | Component of the nuclear corepressor NCOR complex | Sensorineural, adult onset, bilateral, mild to severe | Deafness, Y-linked 2; Y-linked |
| TBL1XR1 | 608628 | Transducin-Beta-Like 1 Receptor 1; nuclear | TBL1XR1/TBLR1/IRA1/C21 | General function in WNT signaling and component of the nuclear corepressor (NCOR) complex | Outer ear malformation, prelingual, unilateral or bilateral, Conductive | Pierpont syndrome; dominant |
| TGFB1 | 190180 | Transforming Growth Factor, Beta-1; secreted | TGFB1, TGFB | Proliferation of mesenchymal and epithelial cell types | Conductive or sensorineural, bilateral, moderate | Camurati-Engelmann disease; dominant, Otosclerosis |
| TGFB1 | 190180 | Transforming Growth Factor, Beta-1; secreted | TGFB1, TGFB | Proliferation of mesenchymal and epithelial cell types | Conductive | Otosclerosis |
| THRB | 190160 | Thyroid Hormone Receptor Beta; nuclear | THRB/ERBA2/ERBAβ | Maturation of auditory system | Prelingual, sensorineural, bilateral, severe | Thyroid hormone resistance, autosomal recessive; recessive |
| THRB | 190160 | Thyroid Hormone Receptor Beta; nuclear | THRB/ERBA2/ERBAβ | Maturation of auditory system | Sensorineural, variable degree | Thyroid hormone resistance; dominant |
| TNFRSF11A | 603499 | Tumor Necrosis Factor Receptor SuperFamily, member 11A; transmembrane | TNFRSF11A/RANK/ODFR/OSTS | Role in auricular ossification, stimulates NF-kappaB signaling | Conductive or mixed, progressive, bilateral, mild to moderate | Paget disease of bone 2, early-onset; dominant |
| TNFRSF11A | 603499 | Tumor Necrosis Factor Receptor SuperFamily, member 11A; transmembrane | TNFRSF11A/RANK/ODFR/OSTS | Role in auricular ossification, stimulates NF-kappaB signaling | Prelingual, mixed, bilateral, mild to moderate, or profound | Osteolysis, familial expansile, dominant |
| TNFRSF11B | 602643 | Tumor Necrosis Factor receptor superfamily, member 11b; secreted | TNFRSF11B/OPG/OCIF | Regulates NF-kappaB signaling as a decoy receptor ligand for TNFRS11A | Sensorineural, prelingual, bilateral, profound | Paget disease of bone 5, juvenile onset; recessive |
OMIM, Online Mendelian Inheritance in Man