310x310px DSS is classified as an autosomal recessive disease(OMIM 224300), but it is also identified as an X-linked recessive inheritance in certain families. The total number of genes that are responsible for causing the disease and the correlation between genotype and phenotype remains unclear. Multiple gene mutations were identified in different patients via whole genome sequencing, therefore it is presumed that DSS is genetically heterogeneous. TCIRG1 mutation The TCIRG1 gene is present in chromosome locus 11q13, which encodes for the a3 subunit of vacuolar H+ ATPase (V-ATPase) that is unique to osteoclasts. The a3 subunit is responsible in anchoring the vacuolar proton pump to the ruffled membrane of osteoclasts. The V-ATPase is important in mediating the transport of hydrogen ions into the resorption lacunae, which is a pit on the bone surface enclosed by the osteoclast for bone resorption. The accumulation of ions in the lacuna facilitates the decomposition of hydroxyapatite crystals by creating an acidic environment, resulting in bone resorption. 310x310px Mutation of the gene results in osteoclast-rich osteopetrosis due to poor translation and altered structure of proton pump structure, which is normally involved in large amounts of osteoclast activity leading to absorption of bone tissue. Mutation of TCIRG1 gene may arise from deletion or gene splicing defects, leading to frame-shifts of the nucleotides of the gene. TCIRG1 mutations illustrate the heterogeneity of DSS through a case study where DSS occurred due to a frameshift mutation, in conjunction with a mutation at an intron located in the gene in one of the alleles of chromosome 11 resulting in a splice site mutation. Despite a frameshift mutation altering the C-terminal of the proton pump, due to increased remnant expression of the wild type transcript, it only resulted in intermediate autosomal recessive DSS due to the partial retainment of vacuolar proton pump function. TNFRSF11A mutation The TNFRSF11A gene is present in chromosome locus 18q21.33, which encodes for the receptor activator of NF-κB (RANK). RANK is expressed in immature osteoclasts, which facilitates osteoclasts maturation upon binding of RANK ligand (RANKL). Binding of RANK ligand mediates the RANK/RANKL/OPG signalling pathway. The pathway mediates osteoclast differentiation and activation by promoting differentiation of precursors into multinucleated osteoclasts, and activating osteoclasts, thereby contributing to bone resorption and remodelling. Health conditions related to genetic changes in TNFRSF11A includes osteopetrosis, osteolysis, and Paget's disease of bone. Multiple reports of gene mutations exists underlining the mutation of the exons and introns leading to aberrant splicing. There are five variants to the TNFRSF11A gene which produces five unique protein iso-forms. The effects of alternative splicing on each variants are unclear. However, it is suggested that such changes lead to different expression patterns of the gene in both space and time. Some mutant splicing variants would undergo nonsense-mediated mRNA decay (NMD), while others would not be subjected to NMD, and instead produce a truncated isoform of the RANK protein. The mutated protein has structural defects hence hinders normal function in the signalling pathway, contributing to development of the disease. Cytogenetic location of SLC29A3 SLC29A3 mutation The SLC29A3 gene is present in chromosome locus10q22.1, which encodes for the equilibrative nucleoside transporter 3 (ENT3), a nucleoside transporter that is present in membranes of mitochondria and lysosomes. ENT3 is responsible for the trafficking of nucleoside, free purines and pyrimidines into the mitochondria and out of lysosomes. Mutations in the gene is often accompanied by histiocytosis-lymphadenopathy plus syndrome, which is characterised by the accumulation of histiocytes leading to lymphadenopathy and other symptoms. Insertion in the coding region was reported in a patient but no records were found in any genetic databanks. Missense mutation was reported to be present in multiple patients and ranked disease-causing by MutationTaster. This insertion mutation is located in the loop within transmembrane helices 1 and 2, while the missense mutations is located in the loop within transmembrane helix 6, 9, and 11. Mutation leads to impaired ENT3 transportation activity, accumulation of nucleotides and nucleoside in lysosomes. As osteoclasts express the SLC29A3 gene, mutation results in incapacitated differentiated osteoclasts’ ability in demineralising calcium phosphate crystal surfaces, disrupted osteoclastic differentiation, and diminished osteoclast counts. The reduced osteoclast differentiation and activity results in decreased demineralisation and reabsorption of bone structures.
Dysosteosclerosis
Osteosclerosis
Microcalcification
Hyperostosis
Osteopoikilosis
Osteolysis
Osteoporosis
Enostosis