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. 2012 Feb 10;90(2):290-4.
doi: 10.1016/j.ajhg.2011.11.024. Epub 2012 Jan 19.

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

Michael A Simpson  1 , Charu Deshpande, Dimitra Dafou, Lisenka E L M Vissers, Wesley J Woollard, Susan E Holder, Gabriele Gillessen-Kaesbach, Ronny Derks, Susan M White, Ruthy Cohen-Snuijf, Sarina G Kant, Lies H Hoefsloot, Willie Reardon, Han G Brunner, Ernie M H F Bongers, Richard C Trembath
Affiliations

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

Michael A Simpson et al. Am J Hum Genet. .

Abstract

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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Figures

Figure 1
Figure 1
Clinical and Genetic Findings of Individuals with Genitopatellar Syndrome (A) Facial features, including a coarse face, a broad bulbous nose, downturned corners of the mouth, and micrognathia (individuals GPS-02 [age 5 months], GPS-03 [age 3 months], and GPS-05 [age 5 months and 25 years, respectively]). (B) Flexion contractures of the knees with skin dimples suggestive of absent patella. (C) Scrotal hypoplasia and cryptorchidism. (D) Observed mutations with respect to the genomic organization of KAT6B and the domain structure of KAT6B.
Figure 2
Figure 2
Evaluation of Mutant KAT6B Transcript Abundance and Detection of Mutant KAT6B Protein (A) Assessment of abundance of total KAT6B transcript in primary skin fibroblasts from individual GPS-02 and the average of two unrelated healthy controls (HDF). Error bars represent standard error of the mean of three independent experiments. (B) Detection of full length and truncated endogenous KAT6B in individual GPS-02 heterozygous for the KAT6B alteration p.Lys1258GlyfsX13.
Figure 3
Figure 3
Effect of KAT6B Mutation p.Lys1258GlyfsX13 on H3 and H4 Acetylation Significant decrease of H3 and H4 acetylation in fibroblasts from individual GPS-02 compared to the average of two HDF (∗p < 0.05; t test). Error bars represent standard deviation of triplicate measurements.
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