Dopachrome tautomerase variants in patients with oculocutaneous albinism

Pennamen, Perrine; Tingaud‐Sequeira, Angèle; Gažová, Iveta; Keighren, Margaret; McKie, Lisa; Marlin, Sandrine; Halem, Souad Gherbi; Kaplan, Josseline; Delevoye, Cédric; Lacombe, Didier; Plaisant, Claudio; Michaud, Vincent; Lasseaux, Eulalie; Javerzat, Sophie; Jackson, Ian J.; Arveiler, Benoı̂t

doi:10.1101/2020.06.26.171223

Cited by 9 publications

(9 citation statements)

References 48 publications

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“…It is involved in the biosynthesis of eumelanin [ 73 ]. Recently, biallelic loss-of-function mutations in DCT have been described in oculocutaneous albinism (OCA8) [ 74 ]. Misexpression of this gene may contribute to the disease or at least the excessively light pigmentation of the iris reported in subjects with congenital miosis.…”

Section: Geneticsmentioning

confidence: 99%

Congenital Microcoria: Clinical Features and Molecular Genetics

Angée

Nédelec

Erjavec

et al. 2021

Genes

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Iris integrity is required to regulate both the amount of light reaching the retina and intraocular pressure (IOP), with elevated IOP being a major risk factor for glaucoma. Congenital microcoria (MCOR) is an extremely rare, autosomal dominant disease affecting iris development and hindering both of these functions. It is characterized by absent or underdeveloped dilator muscle fibers and immaturity of the iridocorneal angle—where the aqueous humor is drained—which play a central role in IOP regulation. The dilator muscle anomaly is manifested in pinhole pupils (<2 mm) and thin transilluminable irises, causing both hemeralopia and photoaversion. Axial myopia and juvenile open-angle glaucoma are very frequent (80% and 30% of all cases, respectively). It has been suggested that the immaturity of the chamber angle contributes to glaucoma, and myopia has been ascribed to photoaversion and elevated IOP. Though possible, these mechanisms are insufficient. The disease has been tied to chromosome 13q32.1 structural variations. In addition to compromising iris development, modification of the 13q32.1 architecture could alter signaling pathways for axial ocular length and IOP regulation. Here, we summarize the clinical, histological, and molecular features of this disease, and we discuss the possible etiology of associated anomalies.

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Section: Geneticsmentioning

confidence: 99%

Congenital Microcoria: Clinical Features and Molecular Genetics

Angée

Nédelec

Erjavec

et al. 2021

Genes

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“…To date, nonsyndromic OCA has been linked to inactivating mutations in eight different genes ( Montoliu et al. , 2014 ; Pennamen et al. , 2020 ).…”

Section: Introductionmentioning

confidence: 99%

SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation

Escobar

et al. 2020

MBoC

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SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations cause oculocutaneous albinism type IV (OCA4) and polymorphisms are associated with pigmentation variation, but the localization, function, and regulation of SLC45A2 and its variants remain unknown. We show that SLC45A2 localizes to a cohort of mature melanosomes that only partially overlaps with those expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that in melanocytes, SLC45A2 expression, like OCA2 expression, results in the deacidification of maturing melanosomes to support melanin synthesis. Interestingly, OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 likely functions later during melanosome maturation than OCA2. Moreover, the light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes due to rapid proteasome-dependent degradation resulting in lower protein expression levels in melanosomes than the dark skin-associated allelic variant. Our data suggest that SLC45A2 maintains melanosome neutralization initially orchestrated by transient OCA2 activity to support melanization at late stages of melanosome maturation, and that a common variant imparts reduced activity due to protein instability.

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“…Currently, we know of at least 22 genes whose mutations are associated with different types of albinism (Garrido et al., 2020; Montoliu et al., 2014; Montoliu & Kelsh, 2014; Montoliu & Marks, 2017; Pennamen, et al., 2020; Pennamen, et al., 2020), resulting in an average prevalence of 1:10,000–20,000 in Western populations.…”

Section: Tyrosinase and Albinismmentioning

confidence: 99%

The structure and function of the mouse tyrosinase locus

Seruggia

Josa

Fernández

et al. 2020

Pigment Cell Melanoma Res

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Tyr is the mouse gene that encodes tyrosinase, an enzyme that triggers the first and rate‐limiting step in the biosynthesis of melanin. Mutations in Tyr might result in non‐functional Tyr protein and, consequently, loss of pigment production. This is a rare genetic condition, known as albinism, described for most animal species and one of the most obvious and simple phenotypes to investigate in model organisms. Mutations in the orthologous human TYR gene are associated with oculocutaneous albinism type 1 (OCA1). Over the last thirty years, the mouse Tyr locus has been studied as a paradigm for how genes and expression domains are organized and regulated in mammalian genomes. This review summarizes the major findings and experimental strategies used, from the production of conventional transgenic mice to the latest CRISPR‐Cas9 genome‐edited animals. The main conclusion inferred from all of these studies, which extends beyond the analysis of the mouse Tyr locus, is the relevance of analyzing non‐coding regulatory DNA elements in their natural chromosomal environment, and not only as randomly inserted transgenes. Further, the identification of evolutionary conserved regulatory sequences might highlight new vulnerable sites in the human TYR gene, whose mutations could also be associated with albinism.

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Dopachrome tautomerase variants in patients with oculocutaneous albinism

Cited by 9 publications

References 48 publications

Congenital Microcoria: Clinical Features and Molecular Genetics

Congenital Microcoria: Clinical Features and Molecular Genetics

SLC45A2 protein stability and regulation of melanosome pH determine melanocyte pigmentation

The structure and function of the mouse tyrosinase locus

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