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Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 domain

Lookup NU author(s): Dr Miranda Splitt

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Abstract

We present a generic, multidisciplinary approach for improving our understanding of novel missense variants in recently discovered disease genes exhibiting genetic heterogeneity, by combining clinical and population genetics with protein structural analysis. Using six newde novo missense diagnoses in TBL1XR1 fromthe Deciphering Developmental Disorders study, together with population variation data, we show that the beta-propeller structure of the ubiquitous WD40 domain provides a convincing way to discriminate between pathogenic and benign variation. Children with likely pathogenic mutations in this gene have severely delayed language development, often accompanied by intellectual disability, autism, dysmorphology and gastrointestinal problems. Amino acids affected by likely pathogenic missense mutations are either crucial for the stability of the fold, forming part of a highly conserved symmetrically repeating hydrogen-bonded tetrad, or located at the top face of the beta-propeller, where 'hotspot' residues affect the binding of beta-catenin to the TBLR1 protein. In contrast, those altered by population variation are significantly less likely to be spatially clustered towards the top face or to be at buried or highly conserved residues. This result is useful not only for interpreting benign and pathogenic missense variants in this gene, but also in other WD40 domains, many of which are associated with disease.


Publication metadata

Author(s): Laskowski RA, Tyagi N, Johnson D, Joss S, Kinning E, McWilliam C, Splitt M, Thornton JM, Firth HV, Wright CF, DDD Study

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2016

Volume: 25

Issue: 5

Pages: 927-935

Print publication date: 01/03/2016

Online publication date: 05/01/2016

Acceptance date: 22/12/2015

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/hmg/ddv625

DOI: 10.1093/hmg/ddv625


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Funding

Funder referenceFunder name
Department of Health
Wellcome Trust
Wellcome Trust Sanger Institute
10/H0305/83Cambridge South REC
HICF-1009-003Health Innovation Challenge Fund
GEN/284/12Republic of Ireland REC
WT098051Wellcome Trust Sanger Institute

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