Exome sequencing identifies a nonsense mutation in Fam46a associated with bone abnormalities in a new mouse model for skeletal dysplasia

Mammalian Genome : Official Journal of the International Mammalian Genome Society
Susanne DienerBettina Lorenz-Depiereux

Abstract

We performed exome sequencing for mutation discovery of an ENU (N-ethyl-N-nitrosourea)-derived mouse model characterized by significant elevated plasma alkaline phosphatase (ALP) activities in female and male mutant mice, originally named BAP014 (bone screen alkaline phosphatase #14). We identified a novel loss-of-function mutation within the Fam46a (family with sequence similarity 46, member A) gene (NM_001160378.1:c.469G>T, NP_001153850.1:p.Glu157*). Heterozygous mice of this mouse line (renamed Fam46a (E157*Mhda)) had significantly high ALP activities and apparently no other differences in morphology compared to wild-type mice. In contrast, homozygous Fam46a (E157*Mhda) mice showed severe morphological and skeletal abnormalities including short stature along with limb, rib, pelvis, and skull deformities with minimal trabecular bone and reduced cortical bone thickness in long bones. ALP activities of homozygous mutants were almost two-fold higher than in heterozygous mice. Fam46a is weakly expressed in most adult and embryonic tissues with a strong expression in mineralized tissues as calvaria and femur. The FAM46A protein is computationally predicted as a new member of the superfamily of nucleotidyltransferase fold proteins,...Continue Reading

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Citations

Oct 7, 2018·Development·Tomoko WatanabeTatsuo Michiue
Jun 21, 2019·The FEBS Journal·Roberta BesioAntonella Forlino
Jan 24, 2018·Journal of Medical Genetics·Mathilde DoyardValérie Cormier-Daire
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Sep 7, 2021·Molecular Metabolism·Nirav Florian ChhabraMartin Hrabě de Angelis

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