[PDF][PDF] De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome

MA Simpson, C Deshpande, D Dafou… - The American Journal of …, 2012 - cell.com
MA Simpson, C Deshpande, D Dafou, LELM Vissers, WJ Woollard, SE Holder…
The American Journal of Human Genetics, 2012cell.com
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 …
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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