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

Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)
Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)
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.
Albinism, Nystagmus, Sequencing, Diagnosis, Tyrosinase
2045-2322
1-9
Norman, Chelsea S.
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O'Gorman, Luke
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Gibson, Jane
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Pengelly, Reuben J.
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Baralle, Diana
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Ratnayaka, J. Arjuna
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Griffiths, Helen
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Rose-Zerilli, Matthew
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Ranger, Megan
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Bunyan, David
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Lee, Helena
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Page, Rhiannon
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Newall, Tutte
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Shawkat, Fatima
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Mattocks, Christopher
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Ward, Daniel
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Ennis, Sarah
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Self, Jay E.
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Norman, Chelsea S.
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O'Gorman, Luke
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Gibson, Jane
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Pengelly, Reuben J.
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Baralle, Diana
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Ratnayaka, J. Arjuna
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Griffiths, Helen
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Rose-Zerilli, Matthew
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Ranger, Megan
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Bunyan, David
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Lee, Helena
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Page, Rhiannon
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Newall, Tutte
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Shawkat, Fatima
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Mattocks, Christopher
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Ward, Daniel
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Ennis, Sarah
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Self, Jay E.
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Norman, Chelsea S., O'Gorman, Luke, Gibson, Jane, Pengelly, Reuben J., Baralle, Diana, Ratnayaka, J. Arjuna, Griffiths, Helen, Rose-Zerilli, Matthew, Ranger, Megan, Bunyan, David, Lee, Helena, Page, Rhiannon, Newall, Tutte, Shawkat, Fatima, Mattocks, Christopher, Ward, Daniel, Ennis, Sarah and Self, Jay E. (2017) Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B). Scientific Reports, 7, 1-9. (doi:10.1038/s41598-017-04401-5).

Record type: Article

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.

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Accepted/In Press date: 5 May 2017
e-pub ahead of print date: 30 June 2017
Keywords: Albinism, Nystagmus, Sequencing, Diagnosis, Tyrosinase
Organisations: Cancer Sciences, Clinical Neurosciences, Human Development & Health, Centre for Biological Sciences, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 408719
URI: https://eprints.soton.ac.uk/id/eprint/408719
ISSN: 2045-2322
PURE UUID: c99b19e1-306b-4d4a-a3eb-c32935a4f3e6
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for Reuben J. Pengelly: ORCID iD orcid.org/0000-0001-7022-645X
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833
ORCID for J. Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938
ORCID for Matthew Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for Helena Lee: ORCID iD orcid.org/0000-0002-2573-9536
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for Jay E. Self: ORCID iD orcid.org/0000-0002-1030-9963

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Date deposited: 27 May 2017 04:02
Last modified: 10 Dec 2019 01:50

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Contributors

Author: Chelsea S. Norman
Author: Luke O'Gorman
Author: Jane Gibson ORCID iD
Author: Diana Baralle ORCID iD
Author: Helen Griffiths
Author: Megan Ranger
Author: David Bunyan
Author: Helena Lee ORCID iD
Author: Rhiannon Page
Author: Tutte Newall
Author: Fatima Shawkat
Author: Christopher Mattocks
Author: Daniel Ward
Author: Sarah Ennis ORCID iD
Author: Jay E. Self ORCID iD

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