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.

Figure 1

Clinical, Radiological, and Histological Features of OPS Cases (A) Antenatal radiological and histological features in two OPS cases from family 5. Skeleton X-rays (I, II) in case 1 showing hypoplastic vertebral bodies, very short metacarpals, horizontal acetabular roof, and metaphyseal irregularities. Growth plate study at the femoral head in sib 2 (15 WG, III) showing nearly absent columnar organization and reduced hypertrophic zone (HY zone) with small reduced number of hypertrophic chondrocytes compared to wild-type growth plate (15 WG, IV). (B) Clinical and radiological findings in case 1 (family 3) at 4 years (I, II, IV, V, VII) and 2 years (III, VI) showing lower limb valgus deformity (I), extremely short hands (II), short metacarpal with metaphyseal cupping and dysplastic carpal ossification (III, IV), severe epiphyseal delay and metaphyseal cupping around the knee (V), and severe platyspondyly (VI, VII).

Figure 2

Localization of INPPL1 Mutations Identified in OPS Individuals