title: Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia.
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.
authors.affiliation: Département de Génétique, Unité INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Fondation Imagine, Hôpital Necker Enfants Malades, Paris 75015, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Huber
authors.forename: Eissa Ali
authors.initials: EA
authors.lastname: Faqeih
authors.forename: Deborah
authors.initials: D
authors.lastname: Bartholdi
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Zvi
authors.initials: Z
authors.lastname: Borochowitz
authors.forename: Denise P
authors.initials: DP
authors.lastname: Cavalcanti
authors.forename: Amandine
authors.initials: A
authors.lastname: Frigo
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Joelle
authors.initials: J
authors.lastname: Roume
authors.forename: Heloísa G
authors.initials: HG
authors.lastname: Santos
authors.forename: Stavit A
authors.initials: SA
authors.lastname: Shalev
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Delezoide
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
chemical_list: D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases