AJHG - An X-Linked Cobalamin Disorder Caused by Mutations in Transcriptional Coregulator HCFC1

AJHG - An X-Linked Cobalamin Disorder Caused by Mutations in Transcriptional Coregulator HCFC1

Copyright 2013 The American Society of Human Genetics All rights reserved.
The American Journal of Human Genetics, Volume 93, Issue 3, 506-514, 5 September 2013

doi:10.1016/j.ajhg.2013.07.022

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Article

An X-Linked Cobalamin Disorder Caused by Mutations in Transcriptional Coregulator HCFC1

Hung-Chun Yu¹, Jennifer L. Sloan², Gunter Scharer^{1, 3, 4, 9}, Alison Brebner⁵, Anita M. Quintana¹, Nathan P. Achilly², Irini Manoli², Curtis R. Coughlin^{1, 3}, Elizabeth A. Geiger¹, Una Schneck¹, David Watkins⁵, Terttu Suormala^{6, 7}, Johan L.K. Van Hove^{1, 3}, Brian Fowler^{6, 7}, Matthias R. Baumgartner^{6, 7, 8}, David S. Rosenblatt⁵, Charles P. Venditti² and Tamim H. Shaikh^{1, 3, 4, ,}

¹ Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
² Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
³ Section of Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA
⁴ Colorado Intellectual and Developmental Disabilities Research Center, University of Colorado School of Medicine, Aurora, CO 80045, USA
⁵ Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada
⁶ Division of Metabolism, University Childrens Hospital, Zürich 8032, Switzerland
⁷ Childrens Research Center, University Childrens Hospital, Zürich 8032, Switzerland
⁸ Zürich Center for Integrative Human Physiology, University of Zürich, Zürich 8057, Switzerland

Corresponding author

⁹ Present address: Medical College of Wisconsin, Department of Pediatrics, Section of Clinical Genetics, Milwaukee, WI 53226, USA

Abstract

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. The most common inborn error of cobalamin metabolism, combined methylmalonic acidemia and hyperhomocysteinemia, cblC type, is caused by mutations in MMACHC. However, several individuals with presumed cblC based on cellular and biochemical analysis do not have mutations in MMACHC. We used exome sequencing to identify the genetic basis of an 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 case. Additional male subjects were ascertained through two international diagnostic laboratories, and 13/17 had one of five distinct missense mutations affecting three highly conserved amino acids within the HCFC1 kelch domain. A common phenotype of severe neurological symptoms including intractable epilepsy and profound neurocognitive impairment, along with variable biochemical manifestations, was observed in all affected subjects compared to individuals with early-onset cblC. The severe reduction in MMACHC mRNA and protein within subject fibroblast lines suggested a role for HCFC1 in transcriptional regulation of MMACHC, which was further supported by the identification of consensus HCFC1 binding sites in MMACHC. Furthermore, siRNA-mediated knockdown of HCFC1 expression resulted in the coordinate downregulation of MMACHC mRNA. This X-linked disorder demonstrates a distinct disease mechanism by which transcriptional dysregulation leads to an inborn error of metabolism with a complex clinical phenotype.