Alternative titles; symbols
HGNC Approved Gene Symbol: SGMS2
SNOMEDCT: 720598005;
Cytogenetic location: 4q25 Genomic coordinates (GRCh38): 4:107,824,563-107,915,047 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q25 | Calvarial doughnut lesions with bone fragility with or without spondylometaphyseal dysplasia | 126550 | Autosomal dominant | 3 |
Sphingomyelin (SM) is a major component of plasma membranes. It is preferentially concentrated in the outer leaflet and has a role in the formation of lipid rafts. SM synthases (EC 2.7.8.27), such as SGMS2, produce SM in the lumen of the Golgi and on the cell surface through the transfer of phosphocholine from phosphatidylcholine onto ceramide, yielding diacylglycerol as a side product (Huitema et al., 2004).
By searching databases for sequences encoding motifs characteristic of SM synthases, Huitema et al. (2004) identified SGMS2, which they called SMS2. The deduced 366-amino acid protein contains 5 membrane-spanning alpha helices connected by hydrophilic extramembrane loops as well as 4 highly conserved motifs, designated D1 to D4. Protease protection analysis of transfected HeLa cells revealed that the C terminus was cytosolic, indicating that the putative active site residues are in the extracellular space. Northern blot analysis of human tissues detected a 1.9-kb transcript in brain, heart, kidney, liver, muscle, and stomach. SGMS2 localized primarily to the plasma membrane as well as to the Golgi apparatus.
Pekkinen et al. (2019) evaluated mRNA expression of Sgms2 in a mouse tissue panel and found highest expression in cortical bone, followed by vertebrae, kidney, and liver. Expression levels were very low in spleen, muscle, heart, brown fat, and thymus. In vitro cultured primary mouse osteoblasts, bone marrow macrophages, and osteoclasts all expressed Sgms2 at similar levels.
Gross (2018) mapped the SGMS2 gene to chromosome 4q25 based on an alignment of the SGMS2 sequence (GenBank BC041369) with the genomic sequence (GRCh38).
By heterologous expression in S. cerevisiae, Huitema et al. (2004) showed that human SGMS2 formed SM in the presence of choline and ceramide. Both phosphatidylcholine and SM itself were utilized as phosphorylcholine group donors, but lysophosphatidylcholine was a very poor substrate, and other donors, including other phospholipids, did not support SM formation. Huitema et al. (2004) concluded that SGMS2 requires 2 fatty chains on the phosphocholine donor molecule for it to be utilized as a substrate. SGMS2 could also catalyze the reverse reaction.
Calvarial Doughnut Lesions with Bone Fragility
In 10 patients from 4 unrelated families with CDL (126550), Pekkinen et al. (2019) identified heterozygosity for the same nonsense mutation in the SGMS2 gene (R50X; 611574.0001). Functional analysis suggested that the underlying cause of osteoporosis and skeletal dysplasia in these patients involves perturbation in sphingomyelin metabolism at the plasma membrane due to a catalytically nonfunctional enzyme.
Calvarial Doughnut Lesions with Bone Fragility and Spondylometaphyseal Dysplasia
In a Dutch mother and son and a Hispanic boy with CDLSMD (see 126550), Pekkinen et al. (2019) identified heterozygosity for 2 different missense mutations in SGMS2: I62S (611574.0002) in the Dutch patients, and M64R (611574.0003) in the Hispanic boy. Functional analysis suggested that the underlying cause of osteoporosis and skeletal dysplasia in these patients involves perturbation in sphingomyelin metabolism at the plasma membrane due to a retention of enzymatically active protein in the endoplasmic reticulum.
In 10 patients from 4 unrelated families (families 1 to 4) with calvarial doughnut lesions with bone fragility (CDL; 126550), including the Finnish family reported by Jaakkola et al. (2009), Pekkinen et al. (2019) identified heterozygosity for a c.148C-T transition (c.148C-T, NM_001136257) in exon 2 of the SGMS2 gene, resulting in an arg50-to-ter (R50X) substitution predicted to yield a truncated protein lacking the entire membrane-spanning core domain, including the active site. The mutation segregated fully with disease in the families and was not found in more than 180 Finnish controls or in the dbSNP, ExAC, or gnomAD databases. Heterologous expression of the mutant in HeLa cells gave rise to a protein that was completely mislocalized in the cytosolic and nuclear compartments. In addition, the mutant failed to support sphingomyelin production in yeast.
In a Dutch mother and son (family 5) with calvarial doughnut lesions with bone fragility, who also had severe short stature and spondylometaphyseal dysplasia (CDLSMD; see 126550), Pekkinen et al. (2019) identified heterozygosity for a c.185T-G transversion (c.185T-G, NM_001136257) in the SGMS2 gene, resulting in an ile62-to-ser (I62S) substitution at a highly conserved residue within a sequence motif just upstream of the first membrane span. The mutation, which arose de novo in the mother, was not found in more than 180 Finnish controls or in the dbSNP, ExAC, or gnomAD databases. Heterologous expression in HeLa cells demonstrated accumulation of the I62S mutant in the endoplasmic reticulum, in contrast to wildtype SGMS2 which predominantly localized at the plasma membrane. Quantitative analysis of patient-derived fibroblasts revealed a marked increase in the rate of sphingomyelin biosynthesis as well as elevated levels of triacylglycerol.
In an 11-year-old Hispanic boy (family 6) with calvarial doughnut lesions with bone fragility, who also had severe short stature and spondylometaphyseal dysplasia (CDLSMD; see 126550), Pekkinen et al. (2019) identified heterozygosity for a de novo c.191T-G transversion (c.191T-G, NM_001136257) in the SGMS2 gene, resulting in a met64-to-arg (M64R) substitution at a highly conserved residue within a sequence motif just upstream of the first membrane span. The mutation was not found in his unaffected parents, 2 unaffected sibs, more than 180 Finnish controls, or in the dbSNP, ExAC, or gnomAD databases. Heterologous expression in HeLa cells demonstrated accumulation of the M64R mutant in the endoplasmic reticulum, in contrast to wildtype SGMS2 which predominantly localized at the plasma membrane. Quantitative analysis of patient-derived fibroblasts revealed a marked increase in the rate of sphingomyelin biosynthesis as well as elevated levels of triacylglycerol.
Gross, M. B. Personal Communication. Baltimore, Md. 4/9/2018.
Huitema, K., van den Dikkenberg, J., Brouwers, J. F. H. M., Holthuis, J. C. M. Identification of a family of animal sphingomyelin synthases. EMBO J. 23: 33-44, 2004. [PubMed: 14685263] [Full Text: https://doi.org/10.1038/sj.emboj.7600034]
Jaakkola, E., Laine, C. M., Mayranpaa, M. K., Falck, A., Ignatius, J., Makitie, O. Calvarial doughnut lesions and osteoporosis: a new three-generation family and review. Am. J. Med. Genet. 149A: 2371-2377, 2009. [PubMed: 19839042] [Full Text: https://doi.org/10.1002/ajmg.a.33040]
Pekkinen, M., Terhal, P. A., Botto, L. D., Henning, P., Makitie, R. E., Roschger, P., Jain, A., Kol. M., Kjellberg, M. A., Paschalis, E. P., van Gassen, K., Murray, M., and 11 others. Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2. JCI Insight 4: 126180, 2019. Note: Electronic Article. [PubMed: 30779713] [Full Text: https://doi.org/10.1172/jci.insight.126180]