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MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness1, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17~92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17~92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17~92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17~92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.
The MIR17HG locus encodes for miR-17~92, a polycistronic miRNA cluster from which six distinct miRNAs are produced (Supplementary Fig. 1). Genetic and functional studies have provided overwhelming evidence that this cluster is a bona fide human oncogene2-10. In addition, loss-of-function experiments in mice have shown that miR-17~92 is essential for mammalian development and that its complete inactivation leads to perinatal lethality11.
Feingold syndrome (MIM164280) is an autosomal dominant syndrome whose core features are microcephaly, relative short stature and digital anomalies, particularly brachymesophalangy of the second and fifth fingers and brachysyndactyly of the toes12,13. Less penetrant defects include oesophageal, duodenal atresia (observed in 30-55% of cases), heart and kidney defects and variable learning disabilities. In approximately 70% of affected families, Feingold syndrome is caused by germline loss-of-function mutations of MYCN (MIM164840) at 2p24.1 (refs. 14,15), but the genetic lesion(s) responsible for the remaining cases have yet to be identified.
We employed high-resolution comparative genomic hybridization (CGH) arrays to perform a genome-wide analysis of ten index subjects with skeletal abnormalities consistent with a diagnosis of Feingold syndrome but who lacked any mutation at the MYCN locus (Supplementary Table 1). This led to the identification of germline hemizygous microdeletions at 13q31.3 in two subjects (AO39 II3 and AO70 II1; Figs. 1 and 2a). The deletion in AO39 II3 spans 2.98 Mb and encompasses three genes: LOC144776, MIR17HG...