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Biallelic mutations in L-dopachrome tautomerase (DCT) cause infantile nystagmus and oculocutaneous albinism

Item Type:Article
Title:Biallelic mutations in L-dopachrome tautomerase (DCT) cause infantile nystagmus and oculocutaneous albinism
Creators Name:Volk, A.E. and Hedergott, A. and Preising, M. and Rading, S. and Fricke, J. and Herkenrath, P. and Nürnberg, P. and Altmüller, J. and von Ameln, S. and Lorenz, B. and Neugebauer, A. and Karsak, M. and Kubisch, C.
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.
Keywords:Base Sequence, Calnexin, Cohort Studies, Congenital Nystagmus, Consanguinity, Gene Expression Regulation, HEK293 Cells, Homozygote, Intramolecular Oxidoreductases, Melanins, Membrane Glycoproteins, Missense Mutation, Monophenol Monooxygenase, Oculocutaneous Albinism, Oxidoreductases, Pedigree, Whole Exome Sequencing
Source:Human Genetics
Page Range:1157-1168
Date:August 2021
Official Publication:https://doi.org/10.1007/s00439-021-02285-0
PubMed:View item in PubMed

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