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Case Reports
. 2014 May 2:15:51.
doi: 10.1186/1471-2350-15-51.

Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome

Clea Bárcena, Víctor Quesada, Annachiara De Sandre-Giovannoli, Diana A Puente, Joaquín Fernández-Toral, Sabine Sigaudy, Anwar Baban, Nicolas Lévy, Gloria Velasco, Carlos López-Otín  1
Affiliations
Case Reports

Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome

Clea Bárcena et al. BMC Med Genet. .

Abstract

Background: SHORT syndrome is a rare autosomal dominant condition whose name is the acronym of short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay (MIM 269880). Additionally, the patients usually present a low birth weight and height, lipodystrophy, delayed bone age, hernias, low body mass index and a progeroid appearance.

Case presentation: In this study, we used whole-exome sequencing approaches in two patients with clinical features of SHORT syndrome. We report the finding of a novel mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8), as well as a recurrent mutation c.1945C > T (p.Arg649Trp) in this gene.

Conclusions: We found a novel frameshift mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8) which consists of a deletion right before the site of substrate recognition. As a consequence, the protein lacks the position that interacts with the phosphotyrosine residue of the substrate, resulting in the development of SHORT syndrome.

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Figures

Figure 1
Figure 1
Facial appearance of patient 1 (A and B) and patient 2 (C-F). The appearance of the patients included in this study shows a clear premature aging phenotype, detectable from the first months of life (patient 2) and striking in adulthood (patient 1).
Figure 2
Figure 2
Sanger sequencing of PIK3R1 (A and B), schematic representation of p85α (C) and spatial modeling of the mutated protein (D). Electropherograms from patients 1 (A) and 2 (B) showing the corresponding mutations in PIK3R1. In patient 1, deletion of 5 nucleotides was detected with Mutation Surveyor software. (C) Schematic representation of the protein mutated in SHORT syndrome patients. The two mutations described in this article are outlined by a red and a yellow star. Both mutations are located in an SH2 region. In patient 1, the mutation results in a truncated protein, whereas in patient 2, it causes an amino acid residue change. (D) Spatial localization of the mutated residues. The mutated residues are shown on the SH2 domain contained in the PDB structure 1PIC. The truncated form resulting after mutation p.Asp643Aspfs*8 is shown in orange. Arginine 649 is shown interacting (yellow dashed line) with the phosphate group of Acetyl-pTyr-Val-Pro-Met-Leu (blue and red sticks). The picture was rendered with PyMOL (v.0.99rc6).
See this image and copyright information in PMC

References

    1. Puente XS, Quesada V, Osorio FG, Cabanillas R, Cadinanos J, Fraile JM, Ordonez GR, Puente DA, Gutierrez-Fernandez A, Fanjul-Fernandez M, Levy N, Freije JM, Lopez-Otin C. Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome. Am J Hum Genet. 2011;15(5):650–656. doi: 10.1016/j.ajhg.2011.04.010. - DOI - PMC - PubMed
    1. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;15(9):790–793. doi: 10.1038/ng.646. - DOI - PMC - PubMed
    1. Gorlin RJ, Cervenka J, Moller K, Horrobin M, Witkop CJ Jr. Malformation syndromes. A selected miscellany. Birth Defects Orig Artic Ser. 1975;15(2):39–50. - PubMed
    1. Koenig R, Brendel L, Fuchs S. SHORT syndrome. Clin Dysmorphol. 2003;15(1):45–49. doi: 10.1097/00019605-200301000-00008. - DOI - PubMed
    1. Chudasama KK, Winnay J, Johansson S, Claudi T, Konig R, Haldorsen I, Johansson B, Woo JR, Aarskog D, Sagen JV, Kahn CR, Molven A, Njolstad PR. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am J Hum Genet. 2013;15(1):150–157. doi: 10.1016/j.ajhg.2013.05.023. - DOI - PMC - PubMed

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