The University of Southampton
University of Southampton Institutional Repository

Mutations in TYR and OCA2 associated with oculocutaneous albinism in Pakistani families

Mutations in TYR and OCA2 associated with oculocutaneous albinism in Pakistani families
Mutations in TYR and OCA2 associated with oculocutaneous albinism in Pakistani families

Background: Oculocutaneous albinism (OCA) is a genetically heterogeneous disorder of abnormal melanin synthesis, resulting in decreased or absent pigmentation of eyes, skin and hair. OCA has been classified based on genetic findings into seven subtypes (OCA 1–7). OCA1 is the most common subtype, accounting for 50% of cases worldwide (Hutton and Spritz, 2008; Rooryck et al., 2008), and is caused by mutations in the tyrosinase (TYR) gene. This study describes genetic investigations in 11 families from Pakistan with individuals with OCA. Methods: Whole genome SNP genotyping for autozygosity mapping was undertaken using the Illumina Human CytoSNP-12 array, and exome sequencing performed using the Illumina TruSight One sequencing panel. For individuals putatively linked to the TYR gene, dideoxy sequencing of TYR was performed using primers targeting all five coding exons and intron-exon splice sites to identify mutations in individuals diagnosed with OCA. Dideoxy sequencing was also performed to confirm the presence and cosegregation of TYR and OCA2 variants identified via exome sequencing. Results: We identified new and previously reported variations in TYR and OCA2 genes in 11 OCA families from Pakistan. One novel missense variant in TYR (NM_000372.4: c.240G>C; p.Trp80Cys), and three novel variants in OCA2 (missense variants NM_000275.2: c.2458T>C; p.Ser820Pro and c.1762C>T; p.Arg588Trp, as well as a frameshift variant c.408_409delTT; p.Arg137Ilefs*83), were observed in five OCA families. In addition, four previously identified variants in TYR (c.649C>T; p.Arg217Trp, c.1255G>A; p.Gly419Arg, c.832C>T; p.Arg278Ter, and c.132T>A p.Ser44Arg) and three previously identified variants in OCA2 (c.1045-15T>G, c.2020C>G; p.Leu674Val and c.1327G>A; p.Val443Ile) were identified in eight OCA families. All affected individuals displayed the cardinal features of OCA with white hair, pale skin, nystagmus and decreased vision. Conclusions: Our findings broaden the molecular spectrum associated with TYR and OCA2 mutations in Pakistani families, aiding the development and refinement of genetic diagnostic and counselling services in Pakistan.

Mutations, OCA, OCA2, Oculocutaneous albinism, Pakistan, TYR
48-55
Arshad, Muhammad Waqar
22f797a1-290e-47b6-b850-30963d4ba269
Harlalka, Gaurav V.
1417f12a-ae2a-40ff-9a26-bf37e7dd9578
Lin, Siying
1bf515d9-21d4-4be5-bce8-f7a719143032
D'Atri, Ilaria
369bbda1-b449-46be-b216-8798b5287a3c
Mehmood, Sarmad
9b252623-07fa-419e-8019-7d70d58715df
Shakil, Muhammad
4c780d3b-2627-4206-8099-d3805737cbbf
Hassan, Muhammad Jawad
0d9c84e2-4a7b-4939-bdec-771199ac6ce5
Chioza, Barry A.
edfb3b9a-5786-4490-a374-9a672060beb2
Self, Jay E.
0f6efc58-ae24-4667-b8d6-6fafa849e389
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
O'Gorman, Luke
6127468d-0693-4a05-b2d0-2f1c2ddc84ff
Norman, Chelsea
f21381a8-b83c-456d-afb2-b7a3aecd3e19
Aman, Tahir
2255341c-009a-4736-8731-580c0201e63b
Ali, Shaheer Sabz
c635aedd-dc19-4afa-ba43-6c4b0337d934
Kaul, Haiba
cc4f6b8f-fe3a-4287-87b7-68cb7a558d6f
Baple, Emma L.
3069a362-2742-42a5-a7a7-e92a9af6fa88
Crosby, Andrew H.
241bc220-d13f-4d1c-8d2b-47ed6fa5cbbd
Ullah, Muhammad Ikram
5b543a6b-ecd8-481c-af2b-da648ade33bd
Shabbir, Muhammad Imran
a2d91f8f-803a-4053-abbd-9fd10dfe6626
Arshad, Muhammad Waqar
22f797a1-290e-47b6-b850-30963d4ba269
Harlalka, Gaurav V.
1417f12a-ae2a-40ff-9a26-bf37e7dd9578
Lin, Siying
1bf515d9-21d4-4be5-bce8-f7a719143032
D'Atri, Ilaria
369bbda1-b449-46be-b216-8798b5287a3c
Mehmood, Sarmad
9b252623-07fa-419e-8019-7d70d58715df
Shakil, Muhammad
4c780d3b-2627-4206-8099-d3805737cbbf
Hassan, Muhammad Jawad
0d9c84e2-4a7b-4939-bdec-771199ac6ce5
Chioza, Barry A.
edfb3b9a-5786-4490-a374-9a672060beb2
Self, Jay E.
0f6efc58-ae24-4667-b8d6-6fafa849e389
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
O'Gorman, Luke
6127468d-0693-4a05-b2d0-2f1c2ddc84ff
Norman, Chelsea
f21381a8-b83c-456d-afb2-b7a3aecd3e19
Aman, Tahir
2255341c-009a-4736-8731-580c0201e63b
Ali, Shaheer Sabz
c635aedd-dc19-4afa-ba43-6c4b0337d934
Kaul, Haiba
cc4f6b8f-fe3a-4287-87b7-68cb7a558d6f
Baple, Emma L.
3069a362-2742-42a5-a7a7-e92a9af6fa88
Crosby, Andrew H.
241bc220-d13f-4d1c-8d2b-47ed6fa5cbbd
Ullah, Muhammad Ikram
5b543a6b-ecd8-481c-af2b-da648ade33bd
Shabbir, Muhammad Imran
a2d91f8f-803a-4053-abbd-9fd10dfe6626

Arshad, Muhammad Waqar, Harlalka, Gaurav V., Lin, Siying, D'Atri, Ilaria, Mehmood, Sarmad, Shakil, Muhammad, Hassan, Muhammad Jawad, Chioza, Barry A., Self, Jay E., Ennis, Sarah, O'Gorman, Luke, Norman, Chelsea, Aman, Tahir, Ali, Shaheer Sabz, Kaul, Haiba, Baple, Emma L., Crosby, Andrew H., Ullah, Muhammad Ikram and Shabbir, Muhammad Imran (2018) Mutations in TYR and OCA2 associated with oculocutaneous albinism in Pakistani families. Meta Gene, 17, 48-55. (doi:10.1016/j.mgene.2018.03.007).

Record type: Article

Abstract

Background: Oculocutaneous albinism (OCA) is a genetically heterogeneous disorder of abnormal melanin synthesis, resulting in decreased or absent pigmentation of eyes, skin and hair. OCA has been classified based on genetic findings into seven subtypes (OCA 1–7). OCA1 is the most common subtype, accounting for 50% of cases worldwide (Hutton and Spritz, 2008; Rooryck et al., 2008), and is caused by mutations in the tyrosinase (TYR) gene. This study describes genetic investigations in 11 families from Pakistan with individuals with OCA. Methods: Whole genome SNP genotyping for autozygosity mapping was undertaken using the Illumina Human CytoSNP-12 array, and exome sequencing performed using the Illumina TruSight One sequencing panel. For individuals putatively linked to the TYR gene, dideoxy sequencing of TYR was performed using primers targeting all five coding exons and intron-exon splice sites to identify mutations in individuals diagnosed with OCA. Dideoxy sequencing was also performed to confirm the presence and cosegregation of TYR and OCA2 variants identified via exome sequencing. Results: We identified new and previously reported variations in TYR and OCA2 genes in 11 OCA families from Pakistan. One novel missense variant in TYR (NM_000372.4: c.240G>C; p.Trp80Cys), and three novel variants in OCA2 (missense variants NM_000275.2: c.2458T>C; p.Ser820Pro and c.1762C>T; p.Arg588Trp, as well as a frameshift variant c.408_409delTT; p.Arg137Ilefs*83), were observed in five OCA families. In addition, four previously identified variants in TYR (c.649C>T; p.Arg217Trp, c.1255G>A; p.Gly419Arg, c.832C>T; p.Arg278Ter, and c.132T>A p.Ser44Arg) and three previously identified variants in OCA2 (c.1045-15T>G, c.2020C>G; p.Leu674Val and c.1327G>A; p.Val443Ile) were identified in eight OCA families. All affected individuals displayed the cardinal features of OCA with white hair, pale skin, nystagmus and decreased vision. Conclusions: Our findings broaden the molecular spectrum associated with TYR and OCA2 mutations in Pakistani families, aiding the development and refinement of genetic diagnostic and counselling services in Pakistan.

Text
Authors accepted proof - Accepted Manuscript
Download (8MB)
Text
pagination_MGENE_419 proofs
Restricted to Repository staff only
Request a copy

More information

Accepted/In Press date: 21 March 2018
e-pub ahead of print date: 22 March 2018
Published date: 1 September 2018
Keywords: Mutations, OCA, OCA2, Oculocutaneous albinism, Pakistan, TYR

Identifiers

Local EPrints ID: 421790
URI: http://eprints.soton.ac.uk/id/eprint/421790
PURE UUID: f239d8eb-f5c8-4704-b0d5-aa5e742ce947
ORCID for Jay E. Self: ORCID iD orcid.org/0000-0002-1030-9963
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

Catalogue record

Date deposited: 27 Jun 2018 16:31
Last modified: 17 Dec 2019 05:26

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×