Mutations in HCFC1 a transcriptional coregulator causes a novel X-linked cobalamin disorder (cblX) with a severe neurological phenotype. T. H. Shaikh1,2, H. C. Yu1, J. L. Sloan3, G. Scharer1, A. Brebner4, A. Quintana1, N. P. Achilly3, I. Manoli3, C. R. Coughlin1, E. A. Geiger1, U. Schneck1, D. Watkins4, J. L. VanHove1, B. Fowler5, M. R. Baumgartner5,6, D. S. Rosenblatt4, C. P. Venditti3 1) Department of Pediatrics, Section of Genetics University of Colorado School of Medicine, Aurora, CO 80045, USA; 2) Colorado Intellectual and Developmental Disabilities Research Center (IDDRC), University of Colorado School of Medicine, Aurora, CO 80045, USA; 3) Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; 4) Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada; 5) Division of Metabolism, Chidren's Research Center, University Children's Hospital, Zürich 8032 , Switzerland,; 6) Zürich Center for Integrative Human Physiology, University of Zürich, Zürich 8057, Switzerland.

   Derivatives of vitamin B12 (cobalamin) are essential cofactors for enzymes required in intermediary metabolism. Defects in cobalamin metabolism lead to disorders characterized by the accumulation of methylmalonic acid and/or homocysteine in blood and urine. Combined methylmalonic acidemia and hyperhomocysteinemia cblC type (cblC) is one of the most common of the inborn errors of cobalamin metabolism, caused by mutations in MMACHC. However, several patients with cblC confirmed by complementation analysis lack mutations in MMACHC, suggesting genetic heterogeneity within this complementation group. We used exome sequencing to identify the genetic basis of a novel, X-linked form of combined methylmalonic acidemia and hyperhomocysteinemia, designated cblX. A missense mutation in a global transcriptional coregulator, HCFC1, was identified in the index patient. Additional male subjects were ascertained through two international diagnostic laboratories and 14/18 had one of 5 distinct missense mutations affecting three highly conserved amino acids (Gln68, Ala73, Ala115) within HCFC1 Kelch domains. A common phenotype of severe neurological symptoms (intractable epilepsy, profound neurocognitive impairment) and mild biochemical manifestations compared to early onset cblC patients was observed in all affected subjects. In two patient fibroblast lines, MMACHC mRNA and protein expression was severely reduced while HCFC1 protein levels remained intact. Furthermore, siRNA knockdown of the HCFC1 resulted in the coordinate down-regulation of MMACHC. This distinct X-linked disorder highlights a novel disease mechanism by which transcriptional dysregulation leads to an inborn error of metabolism with a complex clinical phenotype.

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