Identification of a missense mutation in the tyrosinase gene in a Chinese family with oculocutaneous albinism type 1

Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disease resulting from mutations of the tyrosinase gene (TYR). To elucidate the molecular basis of OCA1 phenotypes, we analysed the early processing and maturation of several different types of mutant tyrosinase with various degrees of structural abnormalities (i.e. two large deletion mutants, two missense mutants that completely destroy catalytic function and three missense mutants that have a temperature-sensitive phenotype). When expressed in COS7 cells, all mutant tyrosinases were sensitive to endoglycosidase H digestion, and immunostaining showed their localization in the endoplasmic reticulum (ER) and their failure to be sorted further to their target organelles. Pulse-chase experiments showed that all mutant tyrosinases were retained by calnexin in the ER and that they were degraded at similarly rapid rates, which coincided with their dissociation from calnexin. Temperature-sensitive mutant enzymes were sorted more efficiently at 31°C than at 37°C, and their degradation was accelerated at 37°C compared with 31°C. Thus in contrast to the current concept that mutant tyrosinases are transported to melanosomes but are functionally inactive there, our results suggest that mutant tyrosinases may not be transported to melanosomes in the first place. We conclude that a significant component of mutant tyrosinase malfunction in OCA1 results from their retention and degradation in the ER compartment. This quality-control process is highly sensitive to minimal changes in protein folding, and so even relatively minor mutations in peripheral sequences of the enzyme not involved with catalytic activity may result in a significant reduction of functional enzyme in melanosomes.

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A novel missense mutation ofTNNI2in a Chinese family cause distal arthrogryposis type 1

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.37391 ◽

2015 ◽

Vol 170 (1) ◽

pp. 135-141 ◽

Cited By ~ 4

Author(s):

Bo Wang ◽

Zhaojing Zheng ◽

Zhigang Wang ◽

Xiaoqing Zhang ◽

Haiou Yang ◽

...

Keyword(s):

Missense Mutation ◽

Chinese Family ◽

Distal Arthrogryposis

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The Tyrosinase Gene and Oculocutaneous Albinism Type 1 (OCA1): A Model for Understanding the Molecular Biology of Melanin Formation

Pigment Cell Research ◽

10.1034/j.1600-0749.2000.130503.x ◽

2000 ◽

Vol 13 (5) ◽

pp. 320-325 ◽

Cited By ~ 133

Author(s):

WILLIAM S. OETTING

Keyword(s):

Molecular Biology ◽

Oculocutaneous Albinism ◽

Melanin Formation ◽

Tyrosinase Gene

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A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse.

Journal of Clinical Investigation ◽

10.1172/jci115075 ◽

1991 ◽

Vol 87 (3) ◽

pp. 1119-1122 ◽

Cited By ~ 65

Author(s):

L B Giebel ◽

R K Tripathi ◽

R A King ◽

R A Spritz

Keyword(s):

Missense Mutation ◽

Oculocutaneous Albinism ◽

Temperature Sensitive ◽

Type I ◽

Human Homologue ◽

Tyrosinase Gene ◽

Siamese Cat

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A novel missense mutation of CRYBA1 in a northern Chinese family with inherited coronary cataract with blue punctate opacities

European Journal of Ophthalmology ◽

10.1177/11206721211008355 ◽

2021 ◽

pp. 112067212110083

Author(s):

Shu-Hua Ni ◽

Juan-Mei Zhang ◽

Jun Zhao

Keyword(s):

Missense Mutation ◽

High Throughput Sequencing ◽

Bioinformatics Analysis ◽

Genetic Defect ◽

Kinase Domain ◽

Chinese Family ◽

Heterozygous Mutation ◽

Scale Invariant ◽

The Family ◽

Northern Chinese

Purpose: To demonstrate the underlying genetic defect that contribute to inherited cataract in a northern Chinese pedigree. Methods: The study recruited a family pedigree with a diagnosis of bilateral coronary cataract with blue punctate opacities. Fourteen family members and 100 healthy volunteers were enrolled. DNA sample of the proband in this family were analyzed by high-throughput sequencing, which was then demonstrated by Sanger sequencing in the remained people in the family and 100 controls. The functional effect of mutant genes was investigated via bioinformatics analysis, including Polymorphism Phenotyping version2 (PolyPhen-2), Protein Variation Effect Analyzer (PROVEAN v1.1.3) Scale-Invariant Feature Transform (SIFT), and Mutation Taster. Results: In this three-generation family, a novel heterozygous mutation was found in the kinase domain of CRYBA1 gene (c.340C > T, p.R114C), which was only detected in patients in the family with inherited cataract and were not detected in the remained people in the family nor in normal people. The pathogenic effect of the mutation was verified via bioinformatics analysis. Conclusion: Our study presented the molecular experiments to confirm that a novel missense mutation of c.340 C > T located in exon 4 of CRYBA1 gene results in a bilateral coronary cataract with blue punctate opacities, which enriches the mutation spectrum of CRYBA1 gene in inherited cataract and deepens the understanding of the pathogenesis of inherited cataract.

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Novel missense mutation of SASH1 in a Chinese family with dyschromatosis universalis hereditaria

BMC Medical Genomics ◽

10.1186/s12920-021-01014-w ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Lu Cao ◽

Ruixue Zhang ◽

Liang Yong ◽

Shirui Chen ◽

Hui Zhang ◽

...

Keyword(s):

Missense Mutation ◽

Sequence Alignment ◽

Multiple Sequence Alignment ◽

Molecular Genetic ◽

Family Members ◽

Clinical Manifestations ◽

Gene Mutations ◽

Mendelian Inheritance ◽

Chinese Family ◽

Multiple Sequence

Abstract Background Dyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH. Methods Sanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations. Results A novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6. Conclusion Although the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene.

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