CXorf56, a dendritic neuronal protein, identified as a new candidate gene for X-linked intellectual disability.

Abstract

Intellectual disability (ID) comprises a large group of heterogeneous disorders, often without a known molecular cause. X-linked ID accounts for 5-10% of male ID cases. We investigated a large, three-generation family with mild ID and behavior problems in five males and one female, with a segregation suggestive for X-linked inheritance. Linkage analysis mapped a disease locus to a 7.6 Mb candidate region on the X-chromosome (LOD score 3.3). Whole-genome sequencing identified a 2 bp insertion in exon 2 of the chromosome X open reading frame 56 gene (CXorf56), resulting in a premature stop codon. This insertion was present in all intellectually impaired individuals and carrier females. Additionally, X-inactivation status showed skewed methylation patterns favoring the inactivation of the mutated allele in the unaffected carrier females. We demonstrate that the insertion leads to nonsense-mediated decay and that CXorf56 mRNA expression is reduced in the impaired males and female. In murine brain slices and primary hippocampal neuronal cultures, CXorf56 protein was present and localized in the nucleus, cell soma, dendrites, and dendritic spines. Although no other families have been identified with pathogenic variants in CXorf56, these results suggest that CXorf56 is the causative gene in this family, and thus a novel candidate gene for X-linked ID with behavior problems.

• Authors: Annemieke J M H Verkerk, Shimriet Zeidler, Guido Breedveld, Lydia Overbeek, Daphne Huigh, Linda Koster, Herma van der Linde, Celine de Esch, Lies-Anne Severijnen, Bert B A de Vries, Sigrid M A Swagemakers, Rob Willemsen, A Jeannette M Hoogeboom, Peter J van der Spek, Ben A Oostra
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 26 Issue 4 Pg. 552-560 (04 2018) ISSN: 1476-5438 [Electronic] England
• PMID: 29374277 (Publication Type: Journal Article)

Chemical References

• Codon, Terminator
• Nerve Tissue Proteins
• Nuclear Proteins
• STEEP1 protein, human

Topics

• Adolescent
• Adult
• Animals
• Cells, Cultured
• Codon, Terminator (genetics)
• DNA Methylation
• Female
• Genetic Diseases, X-Linked (genetics, pathology)
• Humans
• Intellectual Disability (genetics, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Nerve Tissue Proteins (genetics)
• Neurons (metabolism)
• Nonsense Mediated mRNA Decay
• Nuclear Proteins