Alternative titles; symbols
HGNC Approved Gene Symbol: INPPL1
SNOMEDCT: 254068007;
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38): 11:72,223,563-72,239,147 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.4 | Opsismodysplasia | 258480 | Autosomal recessive | 3 |
Hejna et al. (1995) cloned a novel human cDNA that appeared to belong to a family of inositol triphosphate phosphatases. They designated the gene inositol polyphosphate phosphatase like-1 (INPPL1).
Pesesse et al. (1997) cloned the INPPL1 gene, which they called SHIP2, but their clone differed at the N- and C-terminal ends from the sequence of Hejna et al. (1995). SHIP2 encodes a 1,258-amino acid protein with a predicted molecular mass of 142 kD. Northern blot analysis detected particularly high levels of SHIP2 in human heart, skeletal muscle, and placenta. SHIP2 was also expressed in dog thyroid cells in primary culture, where the expression was enhanced in thyroid-stimulating hormone (TSH; see 188540)- and epidermal growth factor (EGF; 131530)-stimulated cells.
Schurmans et al. (1999) reported the cDNA sequence, genomic structure, promoter analysis, and gene expression in the embryo and adult mouse of murine Ship2.
By PCR using primers from the INPPL1 cDNA sequence, Hejna et al. (1995) screened an NIGMS human/rodent somatic cell hybrid mapping panel and assigned the INPPL1 gene to chromosome 11. They narrowed the localization to 11q23 using a chromosome 11-specific deletion panel.
Habib et al. (1998) raised antibodies against SHIP2 to examine the effects of growth factors and insulin (176730) on the metabolism of this protein. Immunoblot analysis revealed that SHIP2 was widely expressed in fibroblast and nonhematopoietic tumor cell lines, unlike the SHIP protein (601582), which was found only in cell lines of hematopoietic origin. The SHIP2 antiserum precipitated a protein of approximately 145 kD, along with an activity which hydrolyzed phosphatidylinositol 3,4,5-triphosphate to phosphatidylinositol 3,4-bisphosphate. Tyrosine phosphorylation of SHIP2 occurred in response to treatment of cells with EGF, platelet-derived growth factor (PDGF; see 190040), nerve growth factor (NGF; 162030), insulin-like growth factor-1 (IGF1; 147440), or insulin. EGF and PDGF induced transient tyrosine phosphorylation of SHIP2, while treatment of cells with NGF, IGF1, or insulin resulted in prolonged tyrosine phosphorylation of SHIP2. Habib et al. (1998) concluded that their data suggests that SHIP2 may play a significant role in regulation of phosphatidylinositol 3-prime-kinase signaling by growth factors and insulin.
Using human epithelial cell lines and primary human corneal and epidermal keratinocytes, Yu et al. (2008) showed that microRNA-184 (MIR184; 613146) interfered with the ability of MIR205 (613147) to downregulate expression of SHIP2. A synthetic antagomir targeting MIR205 or ectopic expression of MIR184 induced SHIP2 expression in keratinocytes, with coordinated damping of AKT (see 164730) signaling and increased apoptosis. Examination of the 3-prime UTR of SHIP2 revealed overlapping binding sites for MIR184 and MIR205. Coexpression of MIR184 with MIR205 reversed MIR205-induced inhibition of a reporter gene containing the SHIP2 3-prime UTR. MIR184 had no direct effect on SHIP2 expression, but instead interfered with MIR205 binding to the 3-prime UTR of SHIP2.
Hasegawa et al. (2011) found that the SYLF domain of human SH3YL1 (617314) bound to liposomes, acidic phospholipids, and phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3). Lipid binding and membrane localization of SH3YL1 required an alpha helix at the N terminus of the SYLF domain, and SH3YL1 was required for dorsal ruffle formation. SH3YL1 formed a complex with SHIP2, and the complex was required for production of PI(3,4)P2. Hasegawa et al. (2011) concluded that the SH3YL1-SHIP2 complex promotes dorsal ruffle formation through conversion PI(3,4,5)P3 to PI(3,4)P2.
Opsismodysplasia
In affected individuals from 7 families with opsismodysplasia (258480), Below et al. (2013) identified homozygosity or compound heterozygosity for mutations in the INPPL1 gene (see, e.g., 600829.0001-600829.0004) that were present in heterozygosity in the unaffected parents for whom DNA was available.
In affected individuals from 10 families with opsismodysplasia, Huber et al. (2013) identified homozygosity or compound heterozygosity for 12 distinct mutations in INPPL1 (see, e.g., 600829.0005-600829.0009), including 2 nonsense, 4 frameshift, 2 splice site, and 4 missense mutations.
In a 33-week-gestation hydropic stillborn (ISDR R01-170) with a clinical diagnosis of Schneckenbecken dysplasia (SHNKND; 269250) in whom Hiraoka et al. (2007) had excluded mutation in the SLC35D1 gene (610804), Lee et al. (2015) identified homozygosity for a splice site mutation in the INPPL1 gene (600829.0004). The authors suggested that this represented a second locus for SHNKND; however, Fradet and Fitzgerald (2017) concluded that additional families with SHNKND would be needed to confirm a role for INPPL1 in that disorder.
Fradet and Fitzgerald (2017) reviewed the variants in the INPPL1 gene identified in patients with opsismodysplasia. The 25 mutations found in 20 families were spread throughout the gene and included 3 nonsense, 1 in-frame, 7 missense, 9 frameshift, and 5 splice site mutations. The majority of the mutations (17/25) were expected to lead to premature stop codons, resulting in a null allele. Six of the 7 missense mutations were located in the catalytic domain and presumably inactivated the phosphatase function of the SHIP2 protein. All patients had mutations in homozygous or compound heterozygous state and heterozygous parents were unaffected, suggesting that SHIP2 needs to be disabled for complete penetrance of the phenotype. No clear genotype-phenotype correlation was noted. The oldest surviving patient reported in the literature was 24 years old and was compound heterozygous for a frameshift and a missense mutation (Gln251His) located outside the catalytic domain, leading the authors to speculate that a small amount of enzyme activity might be enough to ameliorate the severity of the phenotype.
Diabetes Mellitus Type 2
Kagawa et al. (2005) studied the relationship between single-nucleotide polymorphisms (SNPs) in the SHIP2 gene and the pathogenesis of type 2 diabetes (125853) in a Japanese population. They identified 10 polymorphisms including 4 missense mutations. Among them, SNP3 (L632I) was located in the 5-prime-phosphatase catalytic region, and SNP5 (N982S) was adjacent to the phosphotyrosine-binding domain binding consensus motif in the C terminus. SNP3 was found more frequently in control subjects than in type 2 diabetic patients, suggesting that this mutation might protect from insulin resistance. Transfection study showed that expression of SNP3-SHIP2 inhibited insulin-induced PI(3,4,5)-triphosphate production and AKT2 (164731) phosphorylation less potently than expression of wildtype SHIP2 in Chinese hamster ovary cells overexpressing human insulin receptors (CHO-IR). Kagawa et al. (2005) concluded that polymorphisms of SHIP2 are implicated, at least in part, in type 2 diabetes, possibly by affecting the metabolic and/or mitogenic insulin signaling in the Japanese population.
Clement et al. (2001) generated mice lacking the Ship2 gene. Loss of Ship2 led to increased sensitivity to insulin, which was characterized by severe neonatal hypoglycemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death. Adult mice that were heterozygous for the Ship2 mutation had increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the GLUT4 glucose transporter (138190) and increased glycogen synthesis in skeletal muscles. Clement et al. (2001) suggested that the results show that SHIP2 is a potent negative regulator of insulin signaling and insulin sensitivity in vivo. In an erratum, the authors noted that the 7.3-kb genomic DNA fragment deleted in these mice included, in addition to exons 19 to 29 of the Ship2 gene, the last exon of the Phox2a gene (602753); deletion of this exon would give rise to a completely nonfunctional Phox2a protein if expressed. They stated that it was unknown whether the insulin sensitivity observed in their mice resulted from inactivation of either the Ship2 or Phox2a genes alone, or of both genes.
By targeting the translation-initiating ATG codon and deleting the first 18 exons encoding Inppl1, Sleeman et al. (2005) generated Inppl1 -/- mice that were null for Inppl1 mRNA and protein. The mice were viable, had normal glucose and insulin levels, and normal insulin and glucose tolerances. However, they were highly resistant to weight gain when placed on a high-fat diet. Sleeman et al. (2005) suggested that INPPL1 mediates obesity resistance but not changes in glucose and insulin homeostasis.
In an 8-year-old boy and his 2-year-old sister with opsismodysplasia (OPSMD; 258480), born of consanguineous parents of Hispanic and Native American ancestry, Below et al. (2013) identified homozygosity for a 1976C-T transition in exon 17 of the INPPL1 gene, resulting in a pro659-to-leu (P659L) substitution in the catalytic region. The mutation was present in heterozygosity in the unaffected parents and was not found in more than 13,000 chromosomes sequenced as part of the NHLBI Exome Variant Server Sequencing Project. The boy had renal phosphate wasting and hypophosphatemia, whereas his affected sister did not.
In a 3-year-old girl with opsismodysplasia (OPSMD; 258480), born of consanguineous parents of Middle Eastern origin, Below et al. (2013) identified homozygosity for a 545C-A transversion in exon 5 of the INPPL1 gene, resulting in a ser182-to-ter (S182X) substitution predicted to eliminate most of the functional domains of the protein, including the catalytic domain. DNA was unavailable from the unaffected parents; the mutation was not found in more than 13,000 chromosomes sequenced as part of the NHLBI Exome Variant Server Sequencing Project.
In a 19-month-old European American child with opsismodysplasia (OPSMD; 258480), Below et al. (2013) identified homozygosity for a 1-bp deletion at nucleotide 768 in exon 7 of the INPPL1 gene, causing a frameshift predicted to result in a premature termination codon (Glu258AlafsTer45). In an unrelated 16-month-old European American child with opsismodysplasia, the same 1-bp deletion was found in compound heterozygosity with a splice site mutation in intron 21 (2415+1G-A; 600829.0004) of INPPL1. The deletion was maternally inherited in both cases, and the splice site mutation was paternally inherited; no DNA was available from the other father. Neither mutation was found in more than 13,000 chromosomes sequenced as part of the NHLBI Exome Variant Server Sequencing Project.
For discussion of the splice site mutation in the INPPL1 gene (2415+1G-A) that was found in compound heterozygous state in a patient with opsismodysplasia (OPSMD; 258480) by Below et al. (2013), see 600829.0003.
In a 33-week-gestation hydropic stillborn (ISDR R01-170) with a clinical diagnosis of Schneckenbecken dysplasia (SHNKND; 269250) in whom Hiraoka et al. (2007) had excluded mutation in the SLC35D1 gene (610804), Lee et al. (2015) identified homozygosity for the IVS21+1G-A mutation in the INPPL1 gene. Lee et al. (2015) suggested that this represented a second locus for SHNKND; however, Fradet and Fitzgerald (2017) concluded that additional families with SHNKND would be needed to confirm a role for INPPL1 in that disorder.
In a 4-year-old Somali boy with opsismodysplasia (OPSMD; 258480), Huber et al. (2013) identified compound heterozygosity for a 1975C-T transition in exon 17 of the INPPL1 gene, resulting in a pro659-to-ser (P659S) substitution in the 5-phosphatase domain, and a 5-bp deletion (276_280del; 600829.0006) in exon 3, predicted to cause a frameshift (Gln93ProfsTer3) resulting in a truncated protein lacking the proline-rich and SAM domains. The unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 200 ethnically matched controls.
For discussion of the 5-bp deletion in the INPPL1 gene (276_280del) that was found in compound heterozygosity in a patient with opsismodysplasia (OPSMD; 258480) by Huber et al. (2013), see 600829.0005.
In a 19-year-old French Algerian man with opsismodysplasia (OPSMD; 258480), Huber et al. (2013) identified compound heterozygosity for a 1201C-T transition in exon 11 of the INPPL1 gene, resulting in an arg401-to-trp (R401W) substitution, and a 2164T-A transversion in exon 19, resulting in a phe722-to-ile (F722I; 600829.0008) substitution, both in the 5-phosphatase domain. The unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 200 ethnically matched controls. Evaluation of phosphorus and calcium metabolism in this patient was normal, including normal serum and urinary levels of creatinine, calcium, and phosphorus.
For discussion of the phe722-to-ile (F722I) mutation in the INPPL1 gene that was found in compound heterozygous state in a patient with opsismodysplasia (OPSMD; 258480) by Huber et al. (2013), see 600829.0007.
In 3 infants with opsismodysplasia (OPSMD; 258480) from 2 unrelated consanguineous Brazilian families, Huber et al. (2013) identified homozygosity for a 28-bp deletion (94_121del) in exon 1 of the INPPL1 gene, predicted to cause a frameshift (Glu32MetfsTer77) resulting in a truncated protein lacking the proline-rich and SAM domains. One of the infants was stillborn, 1 died a half-hour after birth, and 1 died at 5 days of life.
Below, J. E., Earl, D. L., Shively, K. M., McMillin, M. J., Smith, J. D., Turner, E. H., Stephan, M. J., Al-Gazali, L. I., Hertecant, J. L., Chitayat, D., Unger, S., Cohn, D. H., Krakow, D., Swanson, J. M., Faustman, E. M., Shendure, J., Nickerson, D. A., Bamshad, M. J., University of Washington Center for Mendelian Genomics. Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia. Am. J. Hum. Genet. 92: 137-143, 2013. [PubMed: 23273567] [Full Text: https://doi.org/10.1016/j.ajhg.2012.11.011]
Clement, S., Krause, U., Desmedt, F., Tanti, J.-F., Behrends, J., Pesesse, X., Sasaki, T., Penninger, J., Doherty, M., Malaisse, W., Dumont, J. E., Le Marchand-Brustel, Y., Erneux, C., Hue, L., Schurmans, S. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 409: 92-97, 2001. Note: Erratum: Nature 431: 878 only, 2004. [PubMed: 11343120] [Full Text: https://doi.org/10.1038/35051094]
Fradet, A., Fitzgerald, J. INPPL1 gene mutations in opsismodysplasia. J. Hum. Genet. 62: 135-140, 2017. [PubMed: 27708270] [Full Text: https://doi.org/10.1038/jhg.2016.119]
Habib, T., Hejna, J. A., Moses, R. E., Decker, S. J. Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein. J. Biol. Chem. 273: 18605-18609, 1998. [PubMed: 9660833] [Full Text: https://doi.org/10.1074/jbc.273.29.18605]
Hasegawa, J., Tokuda, E., Tenno, T., Tsujita, K., Sawai, H., Hiroaki, H., Takenawa, T., Itoh, T. SH3YL1 regulates dorsal ruffle formation by a novel phosphoinositide-binding domain. J. Cell Biol. 193: 901-916, 2011. [PubMed: 21624956] [Full Text: https://doi.org/10.1083/jcb.201012161]
Hejna, J. A., Saito, H., Merkens, L. S., Tittle, T. V., Jakobs, P. M., Whitney, M. A., Grompe, M., Friedberg, A. S., Moses, R. E. Cloning and characterization of a human cDNA (INPPL1) sharing homology with inositol polyphosphate phosphatases. Genomics 29: 285-287, 1995. [PubMed: 8530088] [Full Text: https://doi.org/10.1006/geno.1995.1247]
Hiraoka, S., Furuichi, T., Nishimura, G., Shibata, S., Yanagishita, M., Rimoin, D. L., Superti-Furga, A., Nikkels, P. G., Ogawa, M., Katsuyama, K., Toyoda, H., Kinoshita-Toyoda, A., Ishida, N., Isono, K., Sanai, Y., Cohn, D. H., Koseki, H., Ikegawa, S. Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in cartilage and skeletal development in mouse and human. Nature Med. 13: 1363-1367, 2007. [PubMed: 17952091] [Full Text: https://doi.org/10.1038/nm1655]
Huber, C., Faqeih, E. A., Bartholdi, D., Bole-Feysot, C., Borochowitz, Z., Cavalcanti, D. P., Frigo, A., Nitschke, P., Roume, J., Santos, H. G., Shalev, S. A., Superti-Furga, A., Delezoide, A.-L., Le Merrer, M., Munnich, A., Cormier-Daire, V. Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia. Am. J. Hum. Genet. 92: 144-149, 2013. [PubMed: 23273569] [Full Text: https://doi.org/10.1016/j.ajhg.2012.11.015]
Kagawa, S., Sasaoka, T., Yaguchi, S., Ishihara, H., Tsuneki, H., Murakami, S., Fukui, K., Wada, T., Kobayashi, S., Kimura, I., Kobayashi, M. Impact of Src homology 2-containing inositol 5-prime-phosphatase 2 gene polymorphisms detected in a Japanese population on insulin signaling. J. Clin. Endocr. Metab. 90: 2911-2919, 2005. [PubMed: 15687335] [Full Text: https://doi.org/10.1210/jc.2004-1724]
Lee, H., Nevarez, L., Lachman, R. S., Wilcox, W. R., Krakow, D., Cohn, D. H., Univeristy of Washington Center for Mendelian Genomics. A second locus for Schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1). Am. J. Med. Genet. 167A: 2470-2473, 2015. [PubMed: 25997753] [Full Text: https://doi.org/10.1002/ajmg.a.37173]
Pesesse, X., Deleu, S., De Smedt, F., Drayer, L., Erneux, C. Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP. Biochem. Biophys. Res. Commun. 239: 697-700, 1997. [PubMed: 9367831] [Full Text: https://doi.org/10.1006/bbrc.1997.7538]
Schurmans, S., Carrio, R., Behrends, J., Pouillon, V., Merino, J., Clement, S. The mouse SHIP2 (Inppl1) gene: complementary DNA, genomic structure, promoter analysis, and gene expression in the embryo and adult mouse. Genomics 62: 260-271, 1999. [PubMed: 10610720] [Full Text: https://doi.org/10.1006/geno.1999.5995]
Sleeman, M. W., Wortley, K. E., Lai, K.-M. V., Gowen, L. C., Kintner, J., Kline, W. O., Garcia, K., Stitt, T. N., Yancopoulos, G. D., Wiegand, S. J., Glass, D. J. Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity. Nature Med. 11: 199-205, 2005. Note: Erratum: Nature Med. 11: 353 only, 2005. [PubMed: 15654325] [Full Text: https://doi.org/10.1038/nm1178]
Yu, J., Ryan, D. G., Getsios, S., Oliveira-Fernandes, M., Fatima, A., Lavker, R. M. MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia. Proc. Nat. Acad. Sci. 105: 19300-19305, 2008. [PubMed: 19033458] [Full Text: https://doi.org/10.1073/pnas.0803992105]