DO: 0111847;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.12 | Osteogenesis imperfecta, type XIX | 301014 | X-linked recessive | 3 | MBTPS2 | 300294 |
A number sign (#) is used with this entry because of evidence that osteogenesis imperfecta type XIX (OI19) is caused by mutation in the MBTPS2 gene (300294) on chromosome Xp22.
Osteogenesis imperfecta type XIX (OI19) is characterized by prenatal fractures and generalized osteopenia, with severe short stature in adulthood, as well as variable scoliosis and pectal deformity, and marked anterior angulation of the tibia (Lindert et al., 2016).
Lindert et al. (2016) studied 2 unrelated families segregating osteogenesis imperfecta in an X-linked inheritance pattern. The authors examined 6 of 12 affected males from a large Thai pedigree (family I). The proband had prenatal fractures of the ribs and long bones, and examination at age 2 years showed moderate short stature, blue sclerae, pectus carinatum, and bowing of lower extremity long bones. His L2-L4 bone mineral density z-score was -4.7. The proband's mother was healthy with normal weight, height, and bone mineral density. Affected adult males in the family had fractures beginning during gestation, severe short stature, white sclerae, variable scoliosis and pectal deformity, marked anterior angulation of the tibia, and generalized osteopenia. Family II was German and had 2 affected males, the 26-year-old proband and his 68-year-old maternal uncle. At birth, the proband had bowing of humeri, radii, and tibiae, with fractures of femora, ribs, and clavicles as well as generalized osteopenia. Both patients had numerous fractures of upper and lower extremity long bones in childhood, but the number of fractures declined after puberty. Both exhibited white sclerae, kyphoscoliosis with anterior vertebral wedging, and severe short stature, and the uncle had severe pectus excavatum. In both probands, osteoblasts showed broadly defective differentiation, and secretion of type I collagen was significantly reduced.
In a large Thai pedigree segregating OI in an X-linked inheritance pattern, Lindert et al. (2016) performed linkage analysis of the X chromosome and defined a 21.6-Mb critical region on Xp22 between markers DXS7108 and DXS1067, for which they obtained a lod score of 3.31. In a German family with OI, genomewide linkage analysis showed a positive lod score in a 30-Mb region of chromosome X, between SNPs rs11094708 and rs5906168.
In a large Thai pedigree with OI mapping to chromosome Xp22 and negative for mutation in a set of 18 genes associated with OI and bone fragility, Lindert et al. (2016) sequenced the critical region on chromosome X and identified a missense mutation in the MBTPS2 gene (N459S; 300294.0009) that segregated with disease and was not found in 644 X chromosomes of unrelated Thai controls. In a German family with OI mapping to chromosome X, also negative for mutation in the 18-gene set, the authors performed X-exome sequencing and identified another missense variant in MBTPS2 (L505F; 300294.0010) that segregated with disease. Neither mutation was found in public variant databases. Proband osteoblasts showed broadly defective differentiation, and there was decreased proband secretion of type I collagen. The authors stated that this was the first reported form of OI due to X-linked recessive inheritance.
Lindert, U., Cabral, W. A., Ausavarat, S., Tongkobpetch, S., Ludin, K., Barnes, A. M., Yeetong, P., Weis, M., Krabichler, B., Srichomthong, C., Makareeva, E. N., Janecke, A. R., and 9 others. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nature Commun. 7: 11920, 2016. Note: Electronic Article. [PubMed: 27380894] [Full Text: https://doi.org/10.1038/ncomms11920]