Multisystem disorder associated with a pathogenic variant in CLCN7 in the absence of osteopetrosis.
Mol Genet Genomic Med
; 12(7): e2494, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-39056574
ABSTRACT
BACKGROUND:
We clinically and genetically evaluated a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. Whole-exome sequencing revealed a de novo gain-of-function variant, p.Tyr715Cys, in the C-terminal domain of ClC-7 encoded by CLCN7.METHODS:
Nicoli et al. (2019) assessed the functional impact of p.Tyr715Cys by heterologous expression in Xenopus oocytes and evaluating resulting currents.RESULTS:
The variant led to increased outward currents, indicating it underlies the patient's phenotype of lysosomal hyperacidity, storage defects and vacuolization. This demonstrates the crucial physiological role of ClC-7 antiporter activity in maintaining appropriate lysosomal pH.CONCLUSION:
Elucidating mechanisms by which CLCN7 variants lead to lysosomal dysfunction will advance understanding of genotype-phenotype correlations. Identifying modifier genes and compensatory pathways may reveal therapeutic targets. Ongoing functional characterization of variants along with longitudinal clinical evaluations will continue advancing knowledge of ClC-7's critical roles and disease mechanisms resulting from its dysfunction. Expanded cohort studies are warranted to delineate the full spectrum of associated phenotypes.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Canais de Cloreto
Limite:
Child, preschool
/
Humans
/
Male
Idioma:
En
Revista:
Mol Genet Genomic Med
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Taiwan