Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 93, Issue 1, Pages 158-166Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2013.06.005
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Funding
- Government of Canada through Genome Canada
- Canadian Institutes of Health Research (CIHR)
- Ontario Genomics Institute [OGI-049]
- Genome Quebec
- Genome British Columbia
- CR-UK
- Medical Research Council (UK)
- Leukaemia Lymphoma Research (UK)
- CIHR
- CIHR from the Institute of Genetics
- Cancer Research UK [15394] Funding Source: researchfish
- Medical Research Council [G0801130B] Funding Source: researchfish
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SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs*18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657*]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve down-regulation of the PI3K-AKT-mTOR pathway.
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