Bi-allelic null variant in matrix metalloproteinase-15, causes congenital cardiac defect, cholestasis jaundice, and failure to thrive.
Clin Genet
; 101(4): 403-410, 2022 04.
Article
em En
| MEDLINE
| ID: mdl-34988996
ABSTRACT
Here, we delineate the phenotype of two siblings with a bi-allelic frameshift variant in MMP15 gene with congenital cardiac defects, cholestasis, and dysmorphism. Genome sequencing analysis revealed a recently reported homozygous frameshift variant (c.1058delC, p.Pro353Glnfs*102) in MMP15 gene that co-segregates with the phenotype in the family in a recessive mode of inheritance. Relative quantification of MMP15 mRNA showed evidence of degradation of the mutated transcript, presumably by nonsense mediated decay. Likewise, MMP15 p.Gly231Arg, a concurrently reported homozygous missense variant in another patient exhibiting a similar phenotype, was predicted to disrupt zinc ion binding to the MMP-15 enzyme catalytic domain, which is essential for substrate proteolysis, by structural modeling. Previous animal models and cellular findings suggested that MMP15 plays a crucial role in the formation of endocardial cushions. These findings confirm that MMP15 is an important gene in human development, particularly cardiac, and that its loss of function is likely to cause a severe disorder phenotype.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Colestase
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Metaloproteinase 15 da Matriz
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Cardiopatias Congênitas
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Icterícia
Tipo de estudo:
Etiology_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article