Exome sequencing identifies a nonsense mutation in Fam46a associated with bone abnormalities in a new mouse model for skeletal dysplasia
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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, but little is known about its function. Fam46a E157*Mhda mice are the first mouse model for a mutation within the Fam46a gene.
KeywordsExome Sequencing Mouse Line Skeletal Dysplasia Cortical Bone Thickness Intramembranous Ossification
We thank Sandy Lösecke, Sandra Hoffmann, Andreas Mayer, Carola Fischer, Bianca Schmick, Sören Kundt, Anja Wohlbier, Elfi Holupirek, Sebastian Kaidel, Silvia Crowley, and Gerlinde Bergter for excellent technical assistance. We also thank Robert Brommage for scientific discussions and revision of the manuscript. This work was supported by the German Ministry of Education and Research BMBF OSTEOPATH Grant (01EC1006B), Nationales Genomforschungsnetz (NGFN 01GR0430), and NGFNplus Grants (01GS0850 and 01GS0851).
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Conflicts of interest
The authors declare that they have no conflicts of interest.
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