Abstract
Infantile nystagmus syndrome (INS) denominates early-onset, involuntary oscillatory eye movements with different etiologies. Nystagmus is also one of the symptoms in oculocutaneus albinism (OCA), a heterogeneous disease mainly caused by defects in melanin synthesis or melanosome biogenesis. Dopachrome tautomerase (DCT, also called TYRP2) together with tyrosinase (TYR) and tyrosin-related protein 1 (TYRP1) is one of the key enzymes in melanin synthesis. Although DCT´s role in pigmentation has been proven in different species, until now only mutations in TYR and TYRP1 have been found in patients with OCA. Detailed ophthalmological and orthoptic investigations identified a consanguineous family with two individuals with isolated infantile nystagmus and one family member with subtle signs of albinism. By whole-exome sequencing and segregation analysis, we identified the missense mutation c.176G > T (p.Gly59Val) in DCT in a homozygous state in all three affected family members. We show that this mutation results in incomplete protein maturation and targeting in vitro compatible with a partial or total loss of function. Subsequent screening of a cohort of patients with OCA (n = 85) and INS (n = 25) revealed two heterozygous truncating mutations, namely c.876C > A (p.Tyr292*) and c.1407G > A (p.Trp469*), in an independent patient with OCA. Taken together, our data suggest that mutations in DCT can cause a phenotypic spectrum ranging from isolated infantile nystagmus to oculocutaneous albinism.
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Written consent forms of the participating subjects or their legal representatives are available upon request. The raw whole-exome sequencing data are not publicly available due to privacy or ethical restrictions. Processed genetic data generated or analyzed within this study are available upon request.
References
Apkarian P, Reits D, Spekreijse H, Van Dorp D (1983) A decisive electrophysiological test for human albinism. ElectroencephalogrClinNeurophysiol 55:513–531. https://doi.org/10.1016/0013-4694(83)90162-1
CEMAS Working Group (2001) Publication on the classification of eye movement abnormalities and strabismus (CEMAS). National Eye Institute Publications (www.nei.nih.gov), The National Institutes of Health
Cichorek M, Wachulska M, Stasiewicz A, Tyminska A (2013) Skin melanocytes: biology and development. PostepyDermatolAlergol 30:30–41. https://doi.org/10.5114/pdia.2013.33376
Costin GE, Valencia JC, Wakamatsu K, Ito S, Solano F, Milac AL, Vieira WD, Yamaguchi Y, Rouzaud F, Petrescu AJ, Lamoreux ML, Hearing VJ (2005) Mutations in dopachrometautomerase (Dct) affect eumelanin/pheomelanin synthesis, but do not affect intracellular trafficking of the mutant protein. Biochem J 391:249–259. https://doi.org/10.1042/BJ20042070
Federico JR, Krishnamurthy K (2020) Albinism. StatPearls, Treasure Island (FL)
Forssman B, Ringner B (1971) Prevalence and inheritance of congenital nystagmus in a Swedish population. Ann Hum Genet 35:139–147
Gelbart SS, Hoyt CS (1988) Congenital nystagmus: a clinical perspective in infancy. Graefes Arch ClinExpOphthalmol 226:178–180. https://doi.org/10.1007/BF02173313
Gottlob I, Proudlock FA (2014) Aetiology of infantile nystagmus. CurrOpinNeurol 27:83–91. https://doi.org/10.1097/WCO.0000000000000058
Gronskov K, Ek J, Brondum-Nielsen K (2007) Oculocutaneous albinism. Orphanet J Rare Dis 2:43. https://doi.org/10.1186/1750-1172-2-43
Guyonneau L, Murisier F, Rossier A, Moulin A, Beermann F (2004) Melanocytes and pigmentation are affected in dopachrometautomerase knockout mice. Mol Cell Biol 24:3396–3403. https://doi.org/10.1128/mcb.24.8.3396-3403.2004
Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, Musolf A, Li Q, Holzinger E, Karyadi D, Cannon-Albright LA, Teerlink CC, Stanford JL, Isaacs WB, Xu J, Cooney KA, Lange EM, Schleutker J, Carpten JD, Powell IJ, Cussenot O, Cancel-Tassin G, Giles GG, MacInnis RJ, Maier C, Hsieh CL, Wiklund F, Catalona WJ, Foulkes WD, Mandal D, Eeles RA, Kote-Jarai Z, Bustamante CD, Schaid DJ, Hastie T, Ostrander EA, Bailey-Wilson JE, Radivojac P, Thibodeau SN, Whittemore AS, Sieh W (2016) REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 99:877–885. https://doi.org/10.1016/j.ajhg.2016.08.016
Jiao Z, Zhang ZG, Hornyak TJ, Hozeska A, Zhang RL, Wang Y, Wang L, Roberts C, Strickland FM, Chopp M (2006) Dopachrometautomerase (Dct) regulates neural progenitor cell proliferation. Dev Biol 296:396–408. https://doi.org/10.1016/j.ydbio.2006.06.006
Kim YH, Park SJ, Choe SH, Lee JR, Cho HM, Kim SU, Kim JS, Sim BW, Song BS, Lee Y, Jin YB, Hong JJ, Jeong KJ, Kang P, Baek SH, Lee SR, Huh JW, Chang KT (2017) Identification and characterization of the tyrosinase gene (TYR) and its transcript variants (TYR_1 and TYR_2) in the crab-eating macaque (Macacafascicularis). Gene 630:21–27. https://doi.org/10.1016/j.gene.2017.07.047
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315. https://doi.org/10.1038/ng.2892
Kruijt CC, de Wit GC, Bergen AA, Florijn RJ, Schalij-Delfos NE, van Genderen MM (2018) The phenotypic spectrum of albinism. Ophthalmology 125:1953–1960. https://doi.org/10.1016/j.ophtha.2018.08.003
Kumar A, Gottlob I, McLean RJ, Thomas S, Thomas MG, Proudlock FA (2011) Clinical and oculomotor characteristics of albinism compared to FRMD7 associated infantile nystagmus. Invest Ophthalmol Vis Sci 52:2306–2313. https://doi.org/10.1167/iovs.10-5685
Lewis RA (1993) Oculocutaneous Albinism Type 1. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews((R)), Seattle (WA)
Li Y, Jiang L, Wang L, Wang C, Liu C, Guo A, Liu M, Zhang L, Ma C, Zhang X, Gao S, Liu JY (2020) p.His16Arg of STXBP1 (MUNC18–1) associated with syntaxin 3B causes autosomal dominant congenital nystagmus. Front Cell Dev Biol 8: 591781. https://doi.org/10.3389/fcell.2020.591781
Martinez-Garcia M, Montoliu L (2013) Albinism in Europe. J Dermatol 40:319–324. https://doi.org/10.1111/1346-8138.12170
Mayer AK, Mahajnah M, Thomas MG, Cohen Y, Habib A, Schulze M, Maconachie GDE, AlMoallem B, De Baere E, Lorenz B, Traboulsi EI, Kohl S, Azem A, Bauer P, Gottlob I, Sharkia R, Wissinger B (2019) Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus. Brain 142:1528–1534. https://doi.org/10.1093/brain/awz098
McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, Bach M (2015) ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol 130:1–12. https://doi.org/10.1007/s10633-014-9473-7
Montoliu L, Gronskov K, Wei AH, Martinez-Garcia M, Fernandez A, Arveiler B, Morice-Picard F, Riazuddin S, Suzuki T, Ahmed ZM, Rosenberg T, Li W (2014) Increasing the complexity: new genes and new types of albinism. Pigment Cell Melanoma Res 27:11–18. https://doi.org/10.1111/pcmr.12167
Odom JV, Bach M, Brigell M, Holder GE, McCulloch DL, Mizota A, Tormene AP, International Society for Clinical Electrophysiology of V (2016) ISCEV standard for clinical visual evoked potentials: (2016 update). Doc Ophthalmol 133: 1–9 https://doi.org/10.1007/s10633-016-9553-y
O’Donnell FE Jr, Green WR, Fleischman JA, Hambrick GW (1978) X-linked ocular albinism in Blacks. Ocular albinism cum pigmento. Arch Ophthalmol 96:1189–1192. https://doi.org/10.1001/archopht.1978.03910060023005
Olivares C, Solano F (2009) New insights into the active site structure and catalytic mechanism of tyrosinase and its related proteins. Pigment Cell Melanoma Res 22:750–760. https://doi.org/10.1111/j.1755-148X.2009.00636.x
Orlow SJ, Zhou BK, Chakraborty AK, Drucker M, Pifko-Hirst S, Pawelek JM (1994) High-molecular-weight forms of tyrosinase and the tyrosinase-related proteins: evidence for a melanogenic complex. J Invest Dermatol 103:196–201. https://doi.org/10.1111/1523-1747.ep12392743
Pennamen P, Tingaud-Sequeira A, Gazova I, Keighren M, McKie L, Marlin S, GherbiHalem S, Kaplan J, Delevoye C, Lacombe D, Plaisant C, Michaud V, Lasseaux E, Javerzat S, Jackson I, Arveiler B (2020) Dopachrometautomerase variants in patients with oculocutaneous albinism. Genet Med. https://doi.org/10.1038/s41436-020-00997-8
Popa IL, Milac AL, Sima LE, Alexandru PR, Pastrama F, Munteanu CV, Negroiu G (2016) Cross-talk between dopachrometautomerase and caveolin-1 Is melanoma cell phenotype-specific and potentially involved in tumor progression. J BiolChem 291:12481–12500. https://doi.org/10.1074/jbc.M116.714733
Preising MN, Forster H, Gonser M, Lorenz B (2011) Screening of TYR, OCA2, GPR143, and MC1R in patients with congenital nystagmus, macular hypoplasia, and fundus hypopigmentation indicating albinism. Mol Vis 17:939–948
Richards MD, Wong A (2015) Infantile nystagmus syndrome: clinical characteristics, current theories of pathogenesis, diagnosis, and management. Can J Ophthalmol 50:400–408. https://doi.org/10.1016/j.jcjo.2015.07.010
Roffler-Tarlov S, Liu JH, Naumova EN, Bernal-Ayala MM, Mason CA (2013) l-Dopa and the albino riddle: content of l-Dopa in the developing retina of pigmented and albino mice. PLoS ONE 8:e57184. https://doi.org/10.1371/journal.pone.0057184
Rooryck C, Roudaut C, Robine E, Musebeck J, Arveiler B (2006) Oculocutaneous albinism with TYRP1 gene mutations in a Caucasian patient. Pigment Cell Res 19:239–242. https://doi.org/10.1111/j.1600-0749.2006.00298.x
Sampath V, Bedell HE (2002) Distribution of refractive errors in albinos and persons with idiopathic congenital nystagmus. Optom Vis Sci 79:292–299. https://doi.org/10.1097/00006324-200205000-00008
Sarvananthan N, Surendran M, Roberts EO, Jain S, Thomas S, Shah N, Proudlock FA, Thompson JR, McLean RJ, Degg C, Woodruff G, Gottlob I (2009) The prevalence of nystagmus: the Leicestershire nystagmus survey. Invest Ophthalmol Vis Sci 50:5201–5206. https://doi.org/10.1167/iovs.09-3486
Sheth V, Gottlob I, Mohammad S, McLean RJ, Maconachie GD, Kumar A, Degg C, Proudlock FA (2013) Diagnostic potential of iris cross-sectional imaging in albinism using optical coherence tomography. Ophthalmology 120:2082–2090. https://doi.org/10.1016/j.ophtha.2013.03.018
Sivka U, Snoj A, Palandacic A, SusnikBajec S (2013) Identification of candidate genes involved in marble color pattern formation in genus Salmo. Comp BiochemPhysiol Part D GenomProteom 8:244–249. https://doi.org/10.1016/j.cbd.2013.06.003
Sultana H, Seo D, Choi NR, Bhuiyan MSA, Lee SH, Heo KN, Lee JH (2018) Identification of polymorphisms in MITF and DCT genes and their associations with plumage colors in Asian duck breeds. Asian-Aust J AnimSci 31:180–188. https://doi.org/10.5713/ajas.17.0298
Thomas MG, Crosier M, Lindsay S, Kumar A, Araki M, Leroy BP, McLean RJ, Sheth V, Maconachie G, Thomas S, Moore AT, Gottlob I (2014) Abnormal retinal development associated with FRMD7 mutations. Hum Mol Genet 23:4086–4093. https://doi.org/10.1093/hmg/ddu122
Thomas MG, Maconachie G, Sheth V, McLean RJ, Gottlob I (2017) Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing. Eur J Hum Genet 25:725–734. https://doi.org/10.1038/ejhg.2017.44
Tsukamoto K, Jackson IJ, Urabe K, Montague PM, Hearing VJ (1992) A second tyrosinase-related protein, TRP-2, is a melanogenic enzyme termed DOPAchrometautomerase. EMBO J 11:519–526
Wu KC, Lv JN, Yang H, Yang FM, Lin R, Lin Q, Shen RJ, Wang JB, Duan WH, Hu M, Zhang J, He ZL, Jin ZB (2020) Nonhuman primate model of oculocutaneous albinism with TYR and OCA2 mutations. Research (Wash D C) 2020:1658678. https://doi.org/10.34133/2020/1658678
Xiao X, Zhang Q (2009) Iris hyperpigmentation in a Chinese family with ocular albinism and the GPR143 mutation. Am J Med Genet A 149A:1786–1788. https://doi.org/10.1002/ajmg.a.32818
Yamaguchi Y, Hearing VJ (2014) Melanocytes and their diseases. Cold Spring HarbPerspect Med. https://doi.org/10.1101/cshperspect.a017046
Zhang Y, Liu J, Fu W, Xu W, Zhang H, Chen S, Liu W, Peng L, Xiao Y (2017) Comparative transcriptome and DNA methylation analyses of the molecular mechanisms underlying skin color variations in Crucian carp (Carassius carassius L.). BMC Genet 18: 95. https://doi.org/10.1186/s12863-017-0564-9
Acknowledgements
We are indebted to the patients for the participation in this study. For acquisition and illustration of confocal images, we thank Leonore Mensching.
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This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (VO 2028/1–1 to A.V.)
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Volk, A.E., Hedergott, A., Preising, M. et al. Biallelic mutations in l-dopachrome tautomerase (DCT) cause infantile nystagmus and oculocutaneous albinism. Hum Genet 140, 1157–1168 (2021). https://doi.org/10.1007/s00439-021-02285-0
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DOI: https://doi.org/10.1007/s00439-021-02285-0