TY - JOUR
T1 - Bi-allelic null variant in matrix metalloproteinase-15, causes congenital cardiac defect, cholestasis jaundice, and failure to thrive
AU - Abdelrahman, Hanadi A.
AU - Akawi, Nadia
AU - Al-Shamsi, Aisha M.
AU - Ali, Amanat
AU - Al-Jasmi, Fatma
AU - John, Anne
AU - Hertecant, Jozef
AU - Al-Gazali, Lihadh
AU - Ali, Bassam R.
N1 - Funding Information:
We are thankful to the family for their participation in this research study.
Publisher Copyright:
© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
KW - cholestasis
KW - congenital heart disease
KW - endocardial cushions formation
KW - matrix metalloproteinase 15
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U2 - 10.1111/cge.14107
DO - 10.1111/cge.14107
M3 - Article
C2 - 34988996
AN - SCOPUS:85122669563
SN - 0009-9163
VL - 101
SP - 403
EP - 410
JO - Clinical Genetics
JF - Clinical Genetics
IS - 4
ER -