A second locus for schneckenbecken dysplasia identified by a mutation in the gene encoding <i>inositol polyphosphate phosphatase‐like 1</i> (<i>INPPL1</i>)

Lee, Hane; Nevarez, Lisette; Lachman, Ralph S.; Wilcox, William R.; Krakow, Deborah; Cohn, Daniel H.

doi:10.1002/ajmg.a.37173

Cited by 9 publications

(12 citation statements)

References 16 publications

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“…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). Molecular analyses have demonstrated that the negative role of SHIP2 in insulin signaling is caused by SHIP2-mediated inhibition of PI3K-AKT signaling (30,61).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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Sustained activation of extracellular signal–regulated kinase (ERK) drives pathologies caused by mutations in fibroblast growth factor receptors (FGFRs). We previously identified the inositol phosphatase SHIP2 (also known as INPPL1) as an FGFR-interacting protein and a target of the tyrosine kinase activities of FGFR1, FGFR3, and FGFR4. We report that loss of SHIP2 converted FGF-mediated sustained ERK activation into a transient signal and rescued cell phenotypes triggered by pathologic FGFR-ERK signaling. Mutant forms of SHIP2 lacking phosphoinositide phosphatase activity still associated with FGFRs and did not prevent FGF-induced sustained ERK activation, demonstrating that the adaptor rather than the catalytic activity of SHIP2 was required. SHIP2 recruited Src family kinases to the FGFRs, which promoted FGFR-mediated phosphorylation and assembly of protein complexes that relayed signaling to ERK. SHIP2 interacted with FGFRs, was phosphorylated by active FGFRs, and promoted FGFR-ERK signaling at the level of phosphorylation of the adaptor FRS2 and recruitment of the tyrosine phosphatase PTPN11. Thus, SHIP2 is an essential component of canonical FGF-FGFR signal transduction and a potential therapeutic target in FGFR-related disorders.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…INPPL1 mutations have been identified in opsismodysplasia (OPS) [OMIM 258480] (Below et al, 2013, Huber et al, 2013, Iida et al, 2013, Li et al, 2014) and, early in 2015, in Schneckenbecken Dysplasia [OMIM 269250] (Lee et al, 2015). These conditions were not initially considered as a diagnosis and other genes known to be involved in more common severe chondrodyspasias, including FGFR3, COL2A1, COL11A1, COL11A2, DTST and TRIP11 , were sequenced.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a homozygous INPPL1 mutation was described in Schneckenbecken Dysplasia (SD), a severe, autosomal recessive, perinatal lethal dysplasia similar to OPS (Lee et al, 2015). SD demonstrates locus heterogeneity and had previously been shown to be caused by mutations in SLC35D1 , encoding an ER-resident sugar transporter (Hiraoka et al, 2007, Furuichi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…To date, 19 OPS and 1 SD families with INPPL1 mutations have been reported (Below et al, 2013, Huber et al, 2013, Iida et al, 2013, Li et al, 2014, Lee et al, 2015). SHIP2 is one of 10 mammalian inositol polyphosphate 5-phosphatases and functions to dephosphorylate the lipid second messenger phosphoinositol (3,4,5)P3 at the 5-position of the inositol ring to phosphoinositol (3,4)P2 (Pesesse et al, 1997, Habib et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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

Feist

Holden²,

Fitzgerald³

2016

Clinical Dysmorphology

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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.

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“…44 SD presents some features of OPS notably very-short long bones and platyspondyly, but is distinguished from other severe skeletal dysplasias by the presence on radiographs of a medial projection from the ilia that resembles the shape of a snail. SD demonstrates locus heterogeneity and had previously been shown to be caused by mutations in SLC35D1 , encoding an ER-resident sugar transporter essential for glycosaminoglycans synthesis.…”

Section: Mutations In Inppl1mentioning

confidence: 99%

INPPL1 gene mutations in opsismodysplasia

Fradet

Fitzgerald

2016

J Hum Genet

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The INPPL1 (inositol polyphosphate phosphatase-like 1) gene encodes the inositol phosphatase, SHIP2 (for src homology 2 domain-containing inositol phosphatase 2). SHIP2 functions to dephosphorylate, and negatively regulate, the lipid second messenger phosphatidylinositol (3,4,5)P3. SHIP2 has been well studied in the area of insulin resistance and obesity but has roles in cancer and other disorders. Recently, it was reported that mutations in INPPL1 cause opsismodysplasia, a rare, autosomal recessive severe skeletal dysplasia. This review focuses on the mutations associated with opsismodysplasia and explores the role of INPPL1/ SHIP2 in skeletal development.

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A second locus for schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase‐like 1 (INPPL1)

Cited by 9 publications

References 16 publications

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

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

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

INPPL1 gene mutations in opsismodysplasia

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