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

Abstract 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 E...

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Autores principales:	Chelsea S. Norman, Luke O’Gorman, Jane Gibson, Reuben J. Pengelly, Diana Baralle, J. Arjuna Ratnayaka, Helen Griffiths, Matthew Rose-Zerilli, Megan Ranger, David Bunyan, Helena Lee, Rhiannon Page, Tutte Newall, Fatima Shawkat, Christopher Mattocks, Daniel Ward, Sarah Ennis, Jay E. Self
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/eb88692a95b64c0eb747fffe226ced8a
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spelling	oai:doaj.org-article:eb88692a95b64c0eb747fffe226ced8a2021-12-02T11:52:21ZIdentification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)10.1038/s41598-017-04401-52045-2322https://doaj.org/article/eb88692a95b64c0eb747fffe226ced8a2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04401-5https://doaj.org/toc/2045-2322Abstract 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.Chelsea S. NormanLuke O’GormanJane GibsonReuben J. PengellyDiana BaralleJ. Arjuna RatnayakaHelen GriffithsMatthew Rose-ZerilliMegan RangerDavid BunyanHelena LeeRhiannon PageTutte NewallFatima ShawkatChristopher MattocksDaniel WardSarah EnnisJay E. SelfNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chelsea S. Norman Luke O’Gorman Jane Gibson Reuben J. Pengelly Diana Baralle J. Arjuna Ratnayaka Helen Griffiths Matthew Rose-Zerilli Megan Ranger David Bunyan Helena Lee Rhiannon Page Tutte Newall Fatima Shawkat Christopher Mattocks Daniel Ward Sarah Ennis Jay E. Self Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)
description	Abstract 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.
format	article
author	Chelsea S. Norman Luke O’Gorman Jane Gibson Reuben J. Pengelly Diana Baralle J. Arjuna Ratnayaka Helen Griffiths Matthew Rose-Zerilli Megan Ranger David Bunyan Helena Lee Rhiannon Page Tutte Newall Fatima Shawkat Christopher Mattocks Daniel Ward Sarah Ennis Jay E. Self
author_facet	Chelsea S. Norman Luke O’Gorman Jane Gibson Reuben J. Pengelly Diana Baralle J. Arjuna Ratnayaka Helen Griffiths Matthew Rose-Zerilli Megan Ranger David Bunyan Helena Lee Rhiannon Page Tutte Newall Fatima Shawkat Christopher Mattocks Daniel Ward Sarah Ennis Jay E. Self
author_sort	Chelsea S. Norman
title	Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)
title_short	Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)
title_full	Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)
title_fullStr	Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)
title_full_unstemmed	Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)
title_sort	identification of a functionally significant tri-allelic genotype in the tyrosinase gene (tyr) causing hypomorphic oculocutaneous albinism (oca1b)
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/eb88692a95b64c0eb747fffe226ced8a
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Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)

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