New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies
Fabiola Ceroni
(1)
,
Domingo Aguilera-Garcia
(2, 3)
,
Nicolas Chassaing
(4, 5)
,
Dorine Arjanne Bax
(1)
,
Fiona Blanco-Kelly
(2, 3, 6, 7)
,
Patricia Ramos
(2, 3)
,
Maria Tarilonte
(2, 3)
,
Cristina Villaverde
(2, 3)
,
Luciana Rodrigues Jacy da Silva
(2, 3)
,
Maria Juliana Ballesta-Martínez
(8)
,
Maria Jose Sanchez-Soler
(8)
,
Richard James Holt
(1)
,
Lisa Cooper-Charles
(9)
,
Jonathan Bruty
(9)
,
Yvonne Wallis
(9)
,
Dominic Mcmullan
(9)
,
Jonathan Hoffman
(9)
,
David Bunyan
(10)
,
Alison Stewart
(11)
,
Helen Stewart
(6)
,
Katherine Lachlan
(12, 13)
,
Alan Fryer
(14)
,
Victoria Mckay
(14)
,
Joëlle Roume
(15)
,
Pascal Dureau
(16)
,
Anand Saggar
(17)
,
Michael Griffiths
(9)
,
Patrick Calvas
(4, 5)
,
Carmen Ayuso
(2, 3)
,
Marta Corton
(2, 3)
,
Nicola Ragge
(1, 9)
,
Ddd Study
(18)
1
Oxford Brookes University
2 UAM - Universidad Autónoma de Madrid
3 CIBER de Enfermedades Raras (CIBERER)
4 UDEAR - Unité différenciation épidermique et auto-immunité rhumatoïde
5 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
6 Oxford University Hospitals NHS Trust
7 UCL - University College of London [London]
8 University Hospital Murcia
9 Birmingham Women's and Children's NHS Foundation Trust
10 Salisbury District Hospital
11 Sheffield Children's NHS Foundation Trust
12 University Hospital Southampton NHS Foundation Trust
13 University of Southampton
14 Liverpool Women's NHS Foundation Trust
15 CHI Poissy-Saint-Germain
16 Fondation Ophtalmologique Adolphe de Rothschild [Paris]
17 St George's, University of London
18 The Wellcome Trust Sanger Institute [Cambridge]
2 UAM - Universidad Autónoma de Madrid
3 CIBER de Enfermedades Raras (CIBERER)
4 UDEAR - Unité différenciation épidermique et auto-immunité rhumatoïde
5 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
6 Oxford University Hospitals NHS Trust
7 UCL - University College of London [London]
8 University Hospital Murcia
9 Birmingham Women's and Children's NHS Foundation Trust
10 Salisbury District Hospital
11 Sheffield Children's NHS Foundation Trust
12 University Hospital Southampton NHS Foundation Trust
13 University of Southampton
14 Liverpool Women's NHS Foundation Trust
15 CHI Poissy-Saint-Germain
16 Fondation Ophtalmologique Adolphe de Rothschild [Paris]
17 St George's, University of London
18 The Wellcome Trust Sanger Institute [Cambridge]
Nicolas Chassaing
- Fonction : Auteur
- PersonId : 902643
- ORCID : 0000-0003-0234-8820
Patrick Calvas
- Fonction : Auteur
- PersonId : 853869
Carmen Ayuso
- Fonction : Auteur
- PersonId : 759960
- ORCID : 0000-0002-9242-7065
Résumé
GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype-phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.