Brittle bone disease
RESEARCHERS recently discovered a new form of the rare and congenital disorder osteogenesis imperfecta or brittle bone disease that is sex chromosome-linked, providing fresh insights into its genetic diagnosis and facilitating the possible discovery of improved treatment options for patients.
Brittle bone disease is a lifelong condition that affects nearly half a million of the global population.
These patients have extremely fragile bones caused by abnormalities in their COL1A1 and COL1A2 genes, which control collagen production. Collagen is the main protein that is extremely important in making bones strong. The patients’ body tissues containing connective tissues are likewise affected by brittle bone disease.
The study, published on the Web site of Nature Communications last month, was led by researchers from the University of Zurich and the University Children’s Hospital Zurich.
The researchers drew their results from studying a total of 14 patients from two different families. They found out that in both families, the cause of the patients’ osteogenesis imperfecta was mutations in their MBTPS2 gene in the X chromosome. MBTPS2 contains information essential to producing the protein site-2- protease or S2P, whose mutant — discovered to also cause the dermatological disease in humans called IFAP syndrome — was found to weaken bones, according to the researchers.
The affected male members of the studied families have fractures of their limbs and ribs, scoliosis, chest deformity, and short stature.
The males were affected because they only have one X chromosome, while the female carriers have two copies of the X chromosome with one fully functioning copy of the gene, making them unaffected.
“We identified an X-linked form of osteogenesis imperfecta in two independent pedigrees. Phenotypic inheritance pattern, linkage analysis and NGS were used to localize the causative gene in each family to MBTPS2 at Xp22. The gene defects co-segregate with the phenotype in each pedigree and all affected individuals are the sons of obligate carriers,” the researchers wrote.
“This gene identification extends the inheritance pattern of OI to include X-linked recessive. Notably, the OI phenotype of these MBTPS2 defects is distinct from that of PLS3 mutations, which cause an X-linked form of osteoporosis that is mostly apparent in middle-aged adults, but does cause fractures in some children. Unlike MBTPS2 defects reported here which cause moderate to severe OI, PLS3 defects do not cause a generalized bone dysplasia, changes in bone shape or structure, or secondary features of OI,” they added.
The researchers are yet to seek answers as to how and why mutations in MBTPS2 gene can trigger two completely different diseases.
Prior to the study, genes on the autosomal (non- sex) chromosomes were believed to be the cause of all known forms of osteogenesis imperfecta.