Molecular and Functional Studies of Tyrosinase Variants Among Indian Oculocutaneous Albinism Type 1 Patients

Chaki, Moumita; Sengupta, Mainak; Mondal, Maitreyee; Bhattacharya, Abhisek; Mallick, Shampa; Bhadra, Rupak K.; Ray, Kunal

doi:10.1038/jid.2010.274

Cited by 49 publications

(47 citation statements)

References 12 publications

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“…The exact pathogenicity of the variant is yet to be determined, but there is some evidence that there is reduced enzymatic activity of tyrosine hydroxylase and DOPA oxidase when the Tyr192 variant allele was compared with the Ser192 wild-type allele. 23 In NYS-012, we identified a homozygous genomic variant (hg19 chr11:g. 88910354A>G) upstream from the transcription start site for the TYR gene (c.-768A>G; Supplementary Figure S3). This was a rare variant that has previously not been reported in the literature or in control databases (1000 genomes project, NHLBI ESP exomes or Exomes Aggregation Consortium (ExAC)).…”

Section: Resultsmentioning

confidence: 99%

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Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing

et al. 2017

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Infantile nystagmus (IN) is a genetically heterogeneous disorder arising from variants of genes expressed within the developing retina and brain. IN presents a diagnostic challenge and patients often undergo numerous investigations. We aimed to develop and assess the utility of a next-generation sequencing (NGS) panel to enhance the diagnosis of IN. We identified 336 genes associated with IN from the literature and OMIM. NimbleGen Human custom array was used to enrich the target genes and sequencing was performed using HiSeq2000. Using reference genome material (NA12878), we show the sensitivity (98.5%) and specificity (99.9%) of the panel. Fifteen patients with familial IN were sequenced using the panel. Two authors were masked to the clinical diagnosis. We identified variants in 12/15 patients in the following genes: FRMD7 (n=3), CACNA1F (n=2), TYR (n=5), CRYBA1 (n=1) and TYRP1 (n=1). In 9/12 patients, the clinical diagnosis was consistent with the genetic diagnosis. In 3/12 patients, the results from the genetic diagnoses (TYR, CRYBA1 and TYRP1 variants) enabled revision of clinical diagnoses. In 3/15 patients, we were unable to determine a genetic diagnosis. In one patient, copy number variation analysis revealed a FRMD7 deletion. This is the first study establishing the clinical utility of a diagnostic NGS panel for IN. We show that the panel has high sensitivity and specificity. The genetic information from the panel will lead to personalised diagnosis and management of IN and enable accurate genetic counselling. This will allow development of a new clinical care pathway for IN.

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Section: Resultsmentioning

confidence: 99%

“…The Tyr192 variant allele was associated with reduced enzymatic activity of tyrosine hydroxylase and DOPA oxidase when compared with the Ser192 wild-type allele. 23 Further functional work is necessary to understand the exact effects of both these variants on transcription and translation of TYR .…”

Section: Discussionmentioning

confidence: 99%

Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing

et al. 2017

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“…Our data suggest that defects in TYR cause albinism in 58% (36/62) of the cases [1] (and unpublished data; see Figure 1). Functional assays with missense mutations proved that none of mutants are enzymatically active and are retained in the endoplasmic reticulum [1].…”

Section: Resultsmentioning

confidence: 55%

“…Functional assays with missense mutations proved that none of mutants are enzymatically active and are retained in the endoplasmic reticulum [1]. Screening of the remaining cases (43%) revealed OCA2 to be the second common locus followed by SLC45A2 [2] (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Comprehensive analysis of the molecular bases of OCA in Indians

et al. 2010

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“…Functional studies have shown the R402Q polymorphism produces a thermolabile enzyme, retained by the cells endoplasmic reticulum, with a 75% reduction in catalytic activity compared to the wild-type 15, 22, 23 ; and S192Y results in a 40% reduction of tyrosinase enzymatic activity 24 . Multiple OCA1 studies have shown the R402Q allele is strongly associated with albinism patients with only one mutation 12, 17, 20 .…”

Section: Introductionmentioning

confidence: 99%

Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)

Norman

O’Gorman

Gibson

et al. 2017

Sci Rep

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Oculocutaneous albinism (OCA) and ocular albinism (OA) are inherited disorders of melanin biosynthesis, resulting in loss of pigment and severe visual deficits. OCA encompasses a range of subtypes with overlapping, often hypomorphic phenotypes. OCA1 is the most common cause of albinism in European populations and is inherited through autosomal recessive mutations in the Tyrosinase (TYR) gene. However, there is a high level of reported missing heritability, where only a single heterozygous mutation is found in TYR. This is also the case for other OCA subtypes including OCA2 caused by mutations in the OCA2 gene. Here we have interrogated the genetic cause of albinism in a well phenotyped, hypomorphic albinism population by sequencing a broad gene panel and performing segregation studies on phenotyped family members. Of eighteen probands we can confidently diagnose three with OA and OCA2, and one with a PAX6 mutation. Of six probands with only a single heterozygous mutation in TYR, all were found to have the two common variants S192Y and R402Q. Our results suggest that a combination of R402Q and S192Y with a deleterious mutation in a ‘tri-allelic genotype’ can account for missing heritability in some hypomorphic OCA1 albinism phenotypes.

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Molecular and Functional Studies of Tyrosinase Variants Among Indian Oculocutaneous Albinism Type 1 Patients

Abstract: Collagenolytic activities with differentiation of the cultured cells from the murine hair apparatus. J Dermatol Sci 13:83-6 Paus R, Krejci-Papa N, Li L et al. (1994) Correlation of proteolytic activities of organ cultured intact mouse skin with defined hair cycle stages.

Cited by 49 publications

References 12 publications

Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing

Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing

Comprehensive analysis of the molecular bases of OCA in Indians

Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)

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