De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome
SourceAmerican Journal of Human Genetics, 90, 2, (2012), pp. 290-294
Article / Letter to editor
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American Journal of Human Genetics
SubjectIGMD 3: Genomic disorders and inherited multi-system disorders; IGMD 9: Renal disorder; NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders; ONCOL 3: Translational research
Genitopatellar syndrome (GPS) is a rare disorder in which patellar aplasia or hypoplasia is associated with external genital anomalies and severe intellectual disability. Using an exome-sequencing approach, we identified de novo mutations of KAT6B in five individuals with GPS; a single nonsense variant and three frameshift indels, including a 4 bp deletion observed in two cases. All identified mutations are located within the terminal exon of the gene and are predicted to generate a truncated protein product lacking evolutionarily conserved domains. KAT6B encodes a member of the MYST family of histone acetyltranferases. We demonstrate a reduced level of both histone H3 and H4 acetylation in patient-derived cells suggesting that dysregulation of histone acetylation is a direct functional consequence of GPS alleles. These findings define the genetic basis of GPS and illustrate the complex role of the regulation of histone acetylation during development.
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