Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome

Area of Science:

• Genetics
• Developmental Biology
• Epigenetics

Background:

• Genitopatellar syndrome (GPS) is a rare skeletal dysplasia characterized by limb, brain, and genital abnormalities.
• The underlying molecular cause of GPS has remained unknown.

Purpose of the Study:

• To identify the genetic basis of Genitopatellar syndrome.
• To investigate the role of KAT6B in human development and disease.

Main Methods:

• Whole exome sequencing and Sanger sequencing were used to identify mutations.
• Analysis of mutant transcript stability in patient-derived cells.
• Human pathological analysis and mouse expression studies.

Main Results:

• De novo heterozygous truncating mutations in KAT6B were identified in six GPS patients.
• Mutant KAT6B transcripts were stable and not degraded by nonsense-mediated decay.
• KAT6B (Myst4 in mice) expression patterns correlate with GPS-affected tissues, suggesting systemic roles.

Conclusions:

• Mutations in KAT6B are the cause of Genitopatellar syndrome.
• KAT6B plays a critical role in regulating limb, brain, and genital development.
• GPS represents an epigenetic dysregulation of developmental programs due to KAT6B mutations.