Homozygosity mapping of a consanguineous Pakistani family affected with oculocutaneous albinism to Tyrosinase gene

Dear Sir,Iam Haiba Kaul,from the Department of Biochemistry,University of Health Sciences,Lahore,Pakistan.I write to present a study of oculocutaneous albinism（OCA）in consanguineous Pakistani families.OCA is a genetic defect of melanin biosynthesis that mainly affects eyes,skin and hair.

Comment on homozygosity mapping of a consanguineous Pakistani family affected with oculocutaneous albinism to Tyrosinase gene

Dear Editor,I have carefully read the article entitled ＂Homozygosity mapping of a consanguineous Pakistani family affected with oculocutaneous albinism to Tyrosinase gene＂,published by Shakil et al in 2016 and found it very interesting for the scientific community.

Genetic analyses of Chinese patients with digenic oculocutaneous albinism

Background Oculocutaneous albinism （OCA） is a heterogeneous and autosomal recessive disorder in all populations worldwide. The mutational spectra of OCA are population-specific. Some OCA patients carry mutations from different OCA genes. In this study, we investigated the frequency of digenic mutations in Chinese OCA patients. Methods Genomic DNAs were extracted from the blood samples of 184 clinically diagnosed OCA patients and 120 unaffected subjects. The amplified DNA segments of the exons and exon-intron boundaries were screened for mutations of TYR, OCA2, TYRP1, SLC45A2, and HPS1 by direct sequencing. To exclude the previously unidentified alleles from polymorphisms, samples from 120 unaffected controls were sequenced for the same regions of variations. Results In all 184 patients, 134 had two pathologic mutations on one locus. Eleven cases had no apparent pathologic mutations in any of the genes studied. Among the remaining 39 patients who had only one pathologic mutation, five patients （2.7% in total） were found to carry the mutational alleles on a second locus in TYR, OCA2 or SLC45A2. Of the five digenic OCA patients, four patients were clinically diagnosed as OCA2 and one patient as OCAI. A previous unidentified allele p.G188D in SLC45A2 was identified, which was not present in the 120 unaffected controls. Conclusions The identification of the digenic OCA patients suggests the synergistic roles among TYR, OCA2 and SLC45A2 during melanin biosynthesis, which may cause OCA under digenic mutations. This information will be useful for gene diagnosis and genetic counseling of OCA in China.

A novel missense mutation of the TYR gene in a pedigree with oculocutaneous albinism type 1 from China

Background The mutation of the tyrosinase （TYR） gene results in oculocutaneous albinism type 1 （OCA1）, an autosomal recessive genetic disorder. OCA1 is the most common type of OCA in the Chinese population. Hence, the TYR gene was tested in this study. We also delineated the genetic analysis of OCA1 in a Chinese family. Methods Genomic DNA was isolated from the blood leukocytes of a proband and his family. Mutational analysis at the TYR locus by DNA sequencing was used to screen five exons, including the intron/exon junctions. A pedigree chart was drawn and the fundus of the eyes of the proband was also examined. Results A novel missense mutation p.1151S on exon 1, and homozygous TYR mutant alleles were identified in the proband. None of the mutants was identified among the 100 normal control subjects. Genetic analysis of the proband＇s wife showed normal alleles in the TYR gene. Thus, the fetus was predicated a carrier of OCA1 with a normal appearance. Conclusion This study provided new information about a novel mutation, p.1151S, in the TYR gene in a Chinese family with OCAI. Further investigation of the proband would be helpful to determine the effects of this mutation on TYR activity.

Prenatal Genotyping of Four Common Oculocutaneous Albinism Genes in 51 Chinese Families

Oculocutaneous albinism（OCA） is an autosomal recessive disorder characterized by hypopigmentation in eyes,hair and skin,accompanied with vision loss.Currently,six genes have been identified as causative genes for non-syndromic OCA（OCA-1w4,6,7）,and ten genes for syndromic OCA（HPS-1e9,CHS-1）.Genetic counseling of 51 Chinese OCA families（39 OCA-1 with mutations in the TYR gene,6 OCA-2 with mutations in the OCA2 gene,4 OCA-4 with mutations in the SLC45A2 gene,1 HPS-1（Hermanskye Pudlak syndrome-1） with mutation in the HPS1 gene,and 1 mixed OCA-1 and OCA-4） led us to perform the prenatal genetic testing of OCA using amniotic fluid cells through the implementation of our optimized strategy.In our cohort,eleven previously unidentified alleles（PUAs）（5 in TYR,2 in OCA2,and 4 in SLC45A2） were found.Three missense PUAs（p.C112 R,p.H363 R and p.G379 V of TYR） and one in-frame deletional PUA（p.S222 del of SLC24A5） led to fetuses with OCA when co-inherited with other disease causative alleles.Three PUAs（p.P152 H and p.W272 X of TYR,p.A486 T of SLC24A5） identified in the OCA probands did not co-transmit with known pathological alleles and thus gave rise to unaffected fetuses.Four PUAs（p.Q83 X and p.A658 T of TYR,p.G161 R and p.G366 R of SLC24A5） did not transmit to the unaffected fetuses.In addition,the in vitro transfection assays showed that the p.S192 Y variant of TYR produced less pigment compared to the wild-type allele.A fetus with a digenic carrier of OCA-1 and OCA-4 was unaffected.In combination with functional assays,the family inheritance pattern is useful for the evaluation of pathogenicity of PUAs and genetic counseling of OCA.

Application of multiplex ligation-dependent probe amplification in the genetic testing of oculocutaneous albinism

To the Editor: Oculocutaneous albinism (OCA) is an autosomal recessive disorder caused by a group of mutations related to the regulation of melanin synthesis and melanosome biogenesis. The prevalence of OCA worldwide is approximately 1 in 17,000.[1] Other than symptomatic treatment, there is no effective treatment for albinism. Due to the variability in clinical phenotypes, it is difficult to classify sub-types simply by clinical features;therefore, molecular and genetic analyses are the most reliable methods for confirming diagnosis, carrier screening, and pre-natal diagnosis.

Oculocutaneous Albinism with Squamous Cell Carcinoma, Bowen’s Disease and Actinic Keratosis: A Case Report

IntroductionOculocutaneous albinism (OCA) is an autosomal recessive disorder characterized by defects in melanin synthesis that affect the skin,eyes,ears,and hair to varying degrees.Because of the melanin deficiency,albino patients are at high risk for sun-induced skin cancers.Herein,we report a rare case of an OCA type 4 combined with a progressive carcinogenesis for precancerous (actinic keratosis,AK),in situ (Bowen's disease),and invasive status of squamous cell carcinoma (SCC).

Identification of a Homozygous Missense Mutation in the TYR Gene in a Chinese Family with OCA1

Oculocutaneous albinism (OCA)is an autosomal recessive pigmentation abnormality,characterized by variable hair,skin,and ocular hypopigmentation.OCA1 is the most frequent subtype of OCA,caused by mutations in the tyrosinase gene (TYR). In this study,we investigated the genetic mutation of a Chinese family with a female OCA patient who came for genetic counseling before pregnancy.Complete physical examination was performed,and DNA from blood samples was collected from the family members.Mutations of TYR,OCA2,and SLC45A2 genes were examined in the proband, and verified in her parents by Sanger sequencing.Large deletion or duplication of TYR and OCA2 genes was detected by multiplex ligation-dependent probe amplification (MLPA).A homozygous TYR c.307T>C (p.Cys103Arg)missense mutation was identified in the proband,and both parents were heterozygous carriers.No large deletion or duplication was found in the proband.This mutation was absent in 1000G,ExAC,or HGMD database,and multiple lines of in silico tools supported a deleterious effect.These results suggest that TYR c.307T>C mutation might be responsible for OCA1,and our study further expands the mutation spectrum of OCA1 in the Chinese population.