CblX is a New Cobalamin Syndrome Affecting Craniofacial Development

Abstract

Combined methylmalonic acidemia and homocystinuria (cblC type), an inherited disorder of cobalamin (vitamin B12) metabolism, is a rare metabolic and multi‐systemic disease caused by mutations in MMACHC. Patients with cblC can have severe neurodevelopmental defects including microcephaly, hydrocephaly, and seizures as well as renal, cardiac and hematological defects. Recently, two new variants of cblC were discovered and termed cblX and cblX‐like. Rather than being due to mutations in MMACHC, cblX and cblX‐like result from homozygous mutations in the transcription cofactor HCFC1 and its transcription factor partner RONIN (THAP11), respectively. Patients with either HCFC1 or RONIN mutations were shown to have a dramatic reduction in MMACHC transcription. We have known that HCFC1 is an obligatory partner for RONIN and we have previously shown that the HCFC1/RONIN transcriptional complex directly regulates mouse Mmachc expression. These findings suggest that cblX and cblX‐like disorders comprise a novel family of rare and severe cblC‐like disorders that are transcriptional in nature. To better understand the cellular and molecular mechanisms underlying the pathophysiology of these devastating neurodevelopmental diseases, we have generated Hcfc1A115V and RoninF80L mice, which have the same point mutations observed in cblX and cblX‐like patients. Both Hcfc1Y/A115V hemizygous and RoninF80L/F80L homozygous mice exhibit defects in cobalamin metabolism consistent with an inherited vitamin B12 disorder, as well as defects that recapitulate those observed in the human cblX and cblX‐like patients, including severe brain developmental defects, cardiac malformations, and anemia. Additionally, these mice also exhibit craniofacial deformities, a developmental phenotype that has not been previously linked to vitamin B12. Our data identifies, for the first time, a role for RONIN/HCFC1 in craniofacial development. Together, the phenotypic and molecular data confirm that the RoninF80L and Hcfc1A115V mouse models will serve as powerful tools to further uncover the pathophysiology of this complex family of diseases, as well as to achieve a better understanding of the complexities of craniofacial development.Support or Funding InformationThis work is supported by R01 DE028298.