Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities

Quintana, A.M., Yu, H.C., Brebner, A., Pupavac, M., Geiger, E.A., Watson, A., Castro, V.L., Cheung, W., Chen, S.H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D.S., Shaikh, T.H.
Human molecular genetics   26(15): 2838-2849 (Journal)
Registered Authors
Appel, Bruce, Quintana, Anita
phenotype, congenital abnormality, metabolism, mutation, cartilage, craniofacial abnormalities, embryo, genes, homozygote, sequence analysis, rna, vertebrates, zebrafish, transcription factor, cobalamin, brain development, dideoxy chain termination, dna sequencing
MeSH Terms
  • Animals
  • Base Sequence
  • Branchial Region/metabolism
  • Cell Differentiation
  • Child
  • Craniofacial Abnormalities/genetics
  • Fibroblasts
  • Gene Expression Regulation/genetics
  • Host Cell Factor C1/chemistry
  • Host Cell Factor C1/genetics
  • Host Cell Factor C1/metabolism
  • Humans
  • Mutation
  • Primary Cell Culture
  • Repressor Proteins/genetics*
  • Repressor Proteins/metabolism*
  • Transcription, Genetic
  • Vitamin B 12/genetics
  • Vitamin B 12/metabolism*
  • Zebrafish/genetics
28449119 Full text @ Hum. Mol. Genet.
CblX (MIM309541) is an X-linked recessive disorder characterized by defects in cobalamin (vitamin B12) metabolism and other developmental defects. Mutations in HCFC1, a transcriptional co-regulator which interacts with multiple transcription factors, have been associated with cblX. HCFC1 regulates cobalamin metabolism via the regulation of MMACHC expression through its interaction with THAP11, a THAP domain-containing transcription factor. The HCFC1/THAP11 complex potentially regulates genes involved in diverse cellular functions including cell cycle, proliferation, and transcription. Thus, it is likely that mutation of THAP11 also results in biochemical and other phenotypes similar to those observed in patients with cblX. We report a patient who presented with clinical and biochemical phenotypic features that overlap cblX, but who does not have any mutations in either MMACHC or HCFC1. We sequenced THAP11 by Sanger sequencing and discovered a potentially pathogenic, homozygous variant, c.240C>G (p.Phe80Leu). Functional analysis in the developing zebrafish embryo demonstrated that both THAP11 and HCFC1 regulate the proliferation and differentiation of neural precursors, suggesting important roles in normal brain development. The loss of THAP11 in zebrafish embryos results in craniofacial abnormalities including the complete loss of Meckel's cartilage, the ceratohyal, and all of the ceratobranchial cartilages. These data are consistent with our previous work that demonstrated a role for HCFC1 in vertebrate craniofacial development. High throughput RNA-sequencing analysis reveals several overlapping gene targets of HCFC1 and THAP11. Thus, both HCFC1 and THAP11 play important roles in the regulation of cobalamin metabolism as well as other pathways involved in early vertebrate development.
Genes / Markers
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Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes