AnSNX10mutation causes malignant osteopetrosis of infancy

Abstract

Background Osteopetrosis is a life-threatening, rare disorder typically resulting from osteoclast dysfunction and infrequently from failure to commitment to osteoclast lineage. Patients commonly present in infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, and bone marrow failure. In w70% of the patients there is a molecularly defined failure to maintain an acid pH at the osteoclast-bone interface (the ruffled border) which is necessary for the bone resorptive activity. Methods and resultsIn eight patients with infantile osteopetrosis which could be cured by bone marrow transplantation, the study identified by homozygosity mapping in distantly related consanguineous pedigrees a missense mutation in a highly conserved residue in the SNX10 gene. The mutation segregated with the disease in the families and was carried by one of 211 anonymous individuals of the same ethnicity. In the patients' osteoclasts, the mutant SNX10 protein was abnormally abundant and its distribution altered. The patients' osteoclasts were fewer and smaller than control cells, their resorptive capacity was markedly deranged, and the endosomal pathway was perturbed as evidenced by the distribution of internalised dextran. Conclusions SNX10 was recently shown to interact with vacuolar type H + -ATPase (V-ATPase) which pumps protons at the osteoclast-bone interface. Mutations in TCIRG1, the gene encoding a subunit of the V-ATPase complex, account for the majority of cases of osteopetrosis. It is speculated that SNX10 is responsible for the vesicular sorting of V-ATPase from Golgi or for its targeting to the ruffled border. A mutation in SNX10 may therefore result in 'secondary V-ATPase deficiency' with a failure to acidify the resorption lacuna. Determination of the sequence of the SNX10 gene is warranted in molecularly undefined patients with recessive 'pure' osteopetrosis of infancy.

SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity

“…(4) On this basis, we reasoned that SNX10 could be considered a good candidate gene associated with ''Västerbottenian osteopetrosis'' as well as in other cases of ARO with an unknown molecular defect.…”

Regulation of lysosome biogenesis and functions in osteoclasts

“…73,74 Additional studies in other cell types or organisms have shown that SNX10 is interacting with the V-ATPase complex and may be important for its proper localization. 75 The protein kinase C-delta (PKCδ) seems to be an important and specific regulator of cathepsin K exocytosis in osteoclasts.…”

Malignant Infantile Osteopetrosis: A Case Report

“…Klinik formuna bağlı olarak insidansı 1/20000 ile 1/250000 arasındadır. Otozomal resesif tipi, erken çocuklukta klinik veren en sık görülen ağır formdur (1)(2)(3). Anormal osteoklast aktivitesi normal kemik formasyonunu bozar ve sklerotik, frajil kemik oluşumuna neden olur.…”

“…Kemik dansitesinin artışı medüller kaviteyi daraltarak ekstramedüller hematopoez, hepatosplenomegali, anemi ve trombositopeniye yol açar. Büyüme geriliği ve tekrarlayan enfeksiyonlar sıktır (1,2,7). Hastalık fatal seyir-lidir.…”