Novel compound heterozygous mutations in inositol polyphosphate phosphatase-like 1 in a family with severe opsismodysplasia

Abstract

Objective To identify the genetic basis of a severe skeletal lethal dysplasia. The main clinical features of two affected fetuses included: short limbs with flared metaphyses, bowed radii, femora and tibiae, irregular ossification of hands and feet and marked platyspondyly. Methods Affected and non-affected family members were subjected to whole exome sequencing followed by immunoblot analysis on amniocytes isolated from one of the affected individuals. Results Unique compound heterozygous variants in the INPPL1 (inositol polyphosphate phosphatase-like 1) gene encoding the SHIP2 protein were identified in both affected individuals. One variant was inherited from each unaffected parent. Both allelic variants, c.[ 2327-1G>C];[1150_1151delGA], are predicted to result in premature stop codons leading to nonsense-mediated mRNA decay of the mutant alleles and no production of SHIP2. The absence of SHIP2 was confirmed by immunoblot analysis of proband amniocytes. Conclusions This skeletal disorder is caused by the complete absence of SHIP2 protein. INPPL1 mutations have been reported in opsismodysplasia (OPS), an autosomal recessive skeletal dysplasias with significant delayed bone formation. Our finding highlights the critical role that INPPL1/SHIP2 plays in skeletal development.

Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects

“…Western blot and FACS analysis of fibroblasts from three patients with OPS show a lack of expression of SHIP2. This is in agreement with a recent report on amniocytes isolated from a single OPS affected individual where no SHIP2 expression was detected by immunoblot analysis (Feist, Holden, & Fitzgerald, 2016). Our results thus support the hypothesis that SHIP2 is absent at the protein level in OPS patients with nonsense mutations in INPPL1.…”

The inositol phosphatase SHIP2 enables sustained ERK activation downstream of FGF receptors by recruiting Src kinases

“…In addition to altered insulin signaling, the Ship2 −/− mice are about half the size of their wild-type littermates, suggesting a potential role for SHIP2 in the growth of both the axial and appendicular skele-tons. In humans, loss-of-function mutations in SHIP2 cause OPS, an autosomal recessive skeletal dysplasia characterized by severe shortening of all the appendicular bones with radiographic evidence of endochondral ossification delay, extremely short hands, poor bone mineralization, flattening of the spine, and severe midface hypoplasia (62)(63)(64). Histologic analyses of cartilage growth plate morphology in patients with mutations in SHIP2 showed poor organization of the zone of proliferating chondrocytes, near the absence of the zone of hypertrophic chondrocytes, and increased vascular invasion (65,66).…”

INPPL1 gene mutations in opsismodysplasia

“…56 Left, lateral view of spine showing severe platyspondyly. Top right, lateral view of right leg showing bowed femur and flared metaphyses.…”

“…Typical radiographical features include short long bones with markedly delayed epiphyseal mineralization, metaphyseal cupping, short metacarpals and phalanges, and severe platyspondyly. 2–17 Radiographs of an individual with severe OPS are shown in Figure 1. Recurrence in the siblings and consanguinity suggested an autosomal recessive mode of inheritance.…”

“…In 2013, it was reported that OPS is caused by homozygous or compound heterozygous mutations in the INPPL1 (inositol polyphosphate phosphatase-like 1) gene encoding the SHIP2 protein (for src homology 2 domain-containing inositol phosphatase 2). 4,6,7,9,17 However, not all patients have INPPL1 variants suggesting that OPS exhibits genetic heterogeneity. 4,7 …”