Whole exome sequencing reveals a biallelic frameshift mutation in GRXCR2 in hearing impairment in Cameroon

Ambroise Wonkam; Kamogelo Lebeko; Shaheen Mowla; Jean Jacques Noubiap; Mike Chong; Guillaume Pare

doi:10.1002/mgg3.1609

Whole exome sequencing reveals a biallelic frameshift mutation in GRXCR2 in hearing impairment in Cameroon

Mol Genet Genomic Med. 2021 Mar;9(3):e1609. doi: 10.1002/mgg3.1609. Epub 2021 Feb 2.

Authors

Ambroise Wonkam^{1

2}, Kamogelo Lebeko¹, Shaheen Mowla³, Jean Jacques Noubiap⁴, Mike Chong⁵, Guillaume Pare⁵

Affiliations

¹ Department of Medicine, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
² Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
³ Department of Pathology, Division of Haematology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
⁴ Centre for Heart Rhythm Disorders, South Australian Health and Medical Research Institute (SAHMRI, University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia.
⁵ Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada.

Abstract

Background: Hearing impairment (HI) genes are poorly studied in African populations.

Methods: We used whole exome sequencing (WES) to investigate pathogenic and likely pathogenic (PLP) variants in 10 individuals with HI, from four multiplex families from Cameroon, two of which were previously unresolved with a targeted gene enrichment (TGE) panel of 116 genes. In silico protein modelling, western blotting and live imaging of transfected HEK293 cells were performed to study protein structure and functions.

Results: All PLP variants previously identified with TGE were replicated. In one previously unresolved family, we found a homozygous frameshift PLP variant in GRXCR2 (OMIM: 615762), NM_001080516.1(GRXCR2):c.251delC p.(Ile85SerfsTer33), in two affected siblings; and additionally, in 1/80 unrelated individuals affected with non-syndromic hearing impairment (NSHI). The GRXCR2-c.251delC variant introduced a premature stop codon, leading to truncation and loss of a zinc-finger domain. Fluorescence confocal microscopy tracked the wild-type GRXCR2 protein to the cellular membrane, unlike the mutated GRXCR2 protein.

Conclusion: This study confirms GRXCR2 as a HI-associated gene. GRXCR2 should be included to the currently available TGE panels for HI diagnosis.

Keywords: GRXCR2; Africa; Cameroon; hearing impairment; whole exome sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cameroon
Exome Sequencing
Female
Frameshift Mutation*
Glutaredoxins / chemistry
Glutaredoxins / genetics*
Glutaredoxins / metabolism
HEK293 Cells
Hearing Loss / diagnosis
Hearing Loss / genetics*
Humans
Loss of Function Mutation
Male
Protein Domains
Protein Transport

Substances

GRXCR2 protein, human
Glutaredoxins

Abstract

Publication types

MeSH terms

Substances

Grants and funding