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CASE REPORT
Year : 2018  |  Volume : 7  |  Issue : 1  |  Page : 59-62

Decoding of tyrosinase leads to albinism in a nonidentical twin


1 Department of Genetics, Aravind Medical Research Foundation, Dr. G. Venkataswamy Eye Research Institute, Madurai, Tamil Nadu, India
2 Pediatric Clinic, Aravind Eye Hospital, Madurai, Tamil Nadu, India

Date of Web Publication6-Feb-2018

Correspondence Address:
Dr. Periasamy Sundaresan
Department of Genetics, Aravind Medical Research Foundation, Dr. G.Venkataswamy Eye Research Institute, Aravind Eye Hospital, No.1, Anna Nagar, Madurai - 625 020, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_84_17

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  Abstract 


Oculocutaneous albinism (OCA) is an autosomal recessive disorder, phenotypically subcategorized as OCA subtype 1A (OCA-1A) and OCA subtype 1B (OCA-1B). Both the subtypes are genetically caused by the mutations in the tyrosinase (TYR) gene. A 6-month-old nonidentical twin sister was albino who was diagnosed with OCA-1A and had clinical features including hypopigmentation in iris, lid, lashes, skin, nystagmus, and albinotic fundus. Genetic screening revealed the pathogenic mutation at TYR gene locus in albino child, whereas the other child was carrier and holding normal phenotype. We report a differential TYR expression pattern on one of the nonidentical twins.

Keywords: Nonidentical twins, oculocutaneous albinism-1, tyrosinase gene


How to cite this article:
Raj RK, Gopalakrishnan P, Perumalsamy V, Sundaresan P. Decoding of tyrosinase leads to albinism in a nonidentical twin. J Clin Neonatol 2018;7:59-62

How to cite this URL:
Raj RK, Gopalakrishnan P, Perumalsamy V, Sundaresan P. Decoding of tyrosinase leads to albinism in a nonidentical twin. J Clin Neonatol [serial online] 2018 [cited 2018 Apr 24];7:59-62. Available from: http://www.jcnonweb.com/text.asp?2018/7/1/59/224815




  Introduction Top


Albinism is an autosomal recessive inheritance disorder, which is associated with either complete or lack of melanin production and leads to foremost ophthalmological risk such as photophobia, nystagmus, and low visual activity called as oculocutaneous albinism (OCA). There are seven types of OCA categorized as OCA types 1–7. The prevalence of albinism is reported to be 1/20,000 peoples worldwide. OCA-1 is the most common type (50%), which has been clinically subtyped as OCA-1A (OMIM #203100) and OCA-1B (OMIM #606952). OCA-1A (absence of pigmentation) is the most severe phenotype which shows complete loss of tyrosinase (TYR) activity with lifelong absence of melanin synthesis, translucent irides, pale skin, milky white hair, and eyelashes. OCA-1B (reduced pigmentation), previously known as “yellow albinism,” shows partial reduction of the TYR activity. The symptoms of OCA-1B are present perinatally which perhaps increase with age; consequential development of yellow hair pigments during the first few years of life; and gradual accumulation of pigment in skin, hair, and eye. Both the subtypes are caused by mutations throughout the TYR gene located on chromosome 11q14.3. This gene encodes a copper-containing enzyme expressed in melanocytes and regulates a melanin biosynthetic pathway in eye, skin, and hair from birth onward.[1],[2],[3] Mutation in TYR gene was reported as pathogenic in an OCA patient.[4] OCA-1 mutation occurrence rate was found to be high in a particular ethnic group of eastern part of India,[5] South India,[6] and West Bengal.[7] The prevalence of OCA-1 was high in families with consanguineous marriage history in southern part of India in a particular ethnic group.[8]

The majority of OCA-1 cases are autosomal recessive, which means both copies of allele have mutation or each carry one copy of mutated gene. Here, we describe the unique clinical phenotype of nonidentical twin sisters; one sister, the proband of the study, was having varying abnormal color like white skin and hair and another sister was normal in color. Further, we made an attempt to investigate the genotyping of the proband, another twin sister, and their parents.


  Case Report Top


Case presentation

This case report describes a nonconsanguineous and same ethnic group married parents (Madurai, Tamil Nadu; south part of India) who had nonidentical twin sisters (6 months). One twin sister (VII generation) was not responding to bright objects (photophobia) and had abnormal phenotypic symptoms of hypopigmentation in iris, lid, lashes, skin, nystagmus, and albinotic fundus. It confirmed that one of the twins had phenotypic symptoms of OCA-1A. The parents and their nonidentical twins were referred for molecular analysis by a clinician from the Paediatric Clinic, Aravind Eye Hospital, Madurai, Tamil Nadu, India. Written informed consent, for the publication of this report and any additional related information, was taken from the parents (since the proband and the unaffected twin sister were under the age of 16 years) of the twins involved in the study. Familial history of albinism was obtained from the parents; there was a female affected in their IV generation from the proband's maternal relative [Figure 1]a. All the procedures performed in this study involving human participants were in accordance with the ethical standards of the Institutionary Ethics Committee of Aravind Research Medical Foundation and with 1964 Helsinki Declaration and its amendments or comparable ethical standards.
Figure 1: (a) Pedigree was obtained from parents. Dots represent carrier of OCA-1 and solid dark with red color denotes proband of OCA-1. Solid dark represents OCA-affected person from the proband's mother's relative. (b) Chromatogram shows genotype of both parents and their nonidentical twin children. Parents were heterozygous mutant carriers (VI: A3) (VI: B1) (NM_000372.4.c.715C>T; NP_000363.1:P. Arg239Trp). Nonidentical sisters: one twin sister (VII: 1) holding homozygous mutant allele (NM_000372.4.c.715C>T; NP_000363.1:P. Arg239Trp) and the other twin sister (VII: 2) also carrying heterozygous mutant allele (NM_000372.4.c.715C>T; NP_000363.1:P. Arg239Trp). OCA – Oculocutaneous albinism

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  Materials and Methods Top


Isolation and amplification of genomic DNA

Approximately 4–5 ml of peripheral blood was collected from the twin babies and their parents. DNA was extracted by modified salting-out method [9] and quantified with a nano spectrophotometer (NanoDrop Technologies, Inc., Wilmington, DE, USA). TYR gene consists of five exons. All the five coding exons including exon–intron boundaries were polymerase chain reaction (PCR) amplified (Thermal Cycler, Gene Atlas More Details) and subjected directly to Sanger sequencing.[8]

DNA sequencing

The PCR products were purified using an EZ-10 spin-column DNA gel extraction kit (Bio Basic Canada Inc, 20 Konrad Crescent Markham, Ontario, Canada). Big dye termination chemistry method was used for sequencing (3130 Genetic Analyzer, Applied Biosystems, CA, USA). The sequencing results were analyzed by FinchTV version 1.5 (Perkin Elmer Informatics Product Life Cycle) and BLAST.


  Results Top


Sequencing of tyrosinase gene

Sequencing results revealed a missense mutation in exon 1 that was found in proband (affected twin sister) in the form of homozygous mutant allele (TT; NM_000372.4.c.715C>T; NP_000363.1:P. Arg239Trp). The parents and the unaffected twin sister were also carrying a similar heterozygous mutation holding the heterozygous mutant allele (CT; NM_000372.4.c.715C>T; NP_000363.1:P. Arg239Trp) [Figure 1]b. Nakamura et al. reported this missense mutation at position c. 715C>T (NM_000372.4)in exon 1 that substitutes arginine to tryptophan at residue 239 (NP_000363.1:P. R239W) in a patient with Tyrosinase-negative OCA.[10] The resultant missense mutation frequency was 4.34%, which was previously reported from the same ethnic group of peoples from south part of India (Tamil Nadu), Japanese (100%), and Chinese (0.83%).[8] The minor allele frequency (MAF) in ethnically matched controls for T allele (affective recessive mutation) is 0% (MAF <0.01) (https://www.ensembl.org/). In addition, Chaki et al. reported the common single-nucleotide polymorphism markers (c.-533G>C, rs4547091 [NM_000372.4:C.-301C>T] and rs1799989 [NM_000372.4:C.-199C>A]) associated with OCA-1. We also observed these markers in the proband with a homozygous allele, whereas parents and other normal twin sister were holding a heterozygous allele (data not shown).


  Discussion Top


OCA-1 is one of the most common autosomal recessive disorders present from birth. However, numerous reports of OCA-1 might be associated with familial history of either any one affected individual with clinical phenotypes of OCA or genetic carrier and do not show any signs of OCA. As far as accounted, clinical phenotypes were quite distinct: in nonidentical twin sisters, one sister was affected with OCA-2 and the other sister was normal,[11] and in identical twin brothers, one brother was affected with OCA-1 and the other was normal.[12] In addition, genetic analysis on dizygotic twin brothers and sisters with albinism had two missense mutations in p. Pro81 Leu in exon 1 and p. Asn371Thr in exon 3.[13]

In this study, parents carry a heterozygous mutant allele, missense mutation (NM_000372.4.c.715C>T; NP_000363.1:P. Arg239Trp) in exon 1 of TYR gene from the same ethnic group and nonconsanguineous marriage. Their babies were nonidentical twin sisters; one twin sister was also carrying the same heterozygous mutant allele. Another twin sister was carrying a homozygous mutant allele (NM_000372.4.C.715C>T; NP_000363.1:P. Arg239Trp) in exon 1 of TYR gene. Developmental theory state on nonidentical twins shares 50% of a genetic sequence variation.[14] Mendelian theory states that if two genetic carriers (parents) have the same recessive gene mutation, each parent has a chance of passing on either the gene mutation or the wild-type copy of the gene to their baby. This may occur as four possible combinations of passing the genetic information to the baby in every pregnancy; (i) 1 chance in 4 may have 25% probability of nongenetic carrier baby inherited with two copies of the wild-type gene, (ii) 2 chances in 4 (1 chance in 2) may have 50% probability of unaffected genetic carrier baby inherited with a recessive gene mutation or the wild-type copy of the gene similar to the parents, and (iii) 1 chance in 4 may have 25% probability of affected baby inherited with two copies of recessive gene mutation. Nonidentical twin event is that where two separate sperm fertilize two separate eggs. In our case, OCA is affected in one of the nonidentical twin sisters. OCA is an autosomal recessive disorder. This disorder is usually passed by two unaffected genetic carriers (parents) holding a defective allele of the TYR gene containing a recessive mutation. Oculocutaneous albinism subtype 1A (OCA-1A) affected twin baby would be holding two mutated alleles passed from the each of the parents, while another twin baby was not affected and carrier of OCA-1A; would have been holding one normal allele and one mutated allele each passed from parental or maternal transmission.


  Conclusion Top


We report a differential inheritance pattern of TYR gene expression in a nonidentical twin sister. In this scenario which could be reason for one twin sister was affected and another sister was a carrier, perhaps the genetic influences or epigenetic modifications could be one of the decisive factor for OCA-1A phenotype among the twin babies.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Dolinska MB, Kus NJ, Farney SK, Wingfield PT, Brooks BP, Sergeev YV, et al. Oculocutaneous albinism type 1: Link between mutations, tyrosinase conformational stability, and enzymatic activity. Pigment Cell Melanoma Res 2017;30:41-52.  Back to cited text no. 1
    
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Chaki M, Sengupta M, Mukhopadhyay A, Subba Rao I, Majumder PP, Das M, et al. OCA1 in different ethnic groups of India is primarily due to founder mutations in the tyrosinase gene. Ann Hum Genet 2006;70:623-30.  Back to cited text no. 6
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Nakamura E, Miyamura Y, Matsunaga J, Kano Y, Dakeishi-Hara M, Tanita M, et al. A novel mutation of the tyrosinase gene causing oculocutaneous albinism type 1 (OCA1). J Dermatol Sci 2002;28:102-5.  Back to cited text no. 10
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