1. Academic Validation
  2. Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia

Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia

  • Am J Hum Genet. 2013 Jan 10;92(1):144-9. doi: 10.1016/j.ajhg.2012.11.015.
Céline Huber 1 Eissa Ali Faqeih Deborah Bartholdi Christine Bole-Feysot Zvi Borochowitz Denise P Cavalcanti Amandine Frigo Patrick Nitschke Joelle Roume Heloísa G Santos Stavit A Shalev Andrea Superti-Furga Anne-Lise Delezoide Martine Le Merrer Arnold Munnich Valérie Cormier-Daire
Affiliations

Affiliation

  • 1 Département de Génétique, Unité INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hôpital Necker Enfants Malades, Paris 75015, France.
Abstract

Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome Sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating Enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this Enzyme in endochondral ossification.

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