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The locomotor system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Osteopetrosis is a bone disease characterized by increased bone density due to defective osteoclastic activity. This leads to increased risk of fracture. The severest form is usually inherited as an autosomal recessive condition and presents in infancy. In the majority of cases there are mutations in the CLCN7 gene. There is failure of resorption of the fetal cartilaginous model of bones, so that the marrow cavities fail to form. Severe anaemia, leukopaenia and increased risk of bleeding develop. The bones are radio-opaque and show evidence of abnormal remodelling. Despite the increased bone density the bones are structurally abnormal and subject to pathological fracture. Skull involvement with narrowing of exit foramina may result in deafness or blindness. Patients with severe disease may be treated by haemopoietic stem cell transplant. Donor osteoclasts derived from marrow precursors resorb the cartilaginous matrix and allow remodelling. Milder forms inherited as autosomal dominant traits are often not recognized until adult life, typically after a fracture. The precise pathogenic mechanisms in humans remain uncertain in most cases. In one mild form, an absence of osteoclast carbonic anhydrase activity is responsible.
A new set of clinical tools for physicians
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
There are too many examples of WES successes to list all of them here, which can be placed in different categories based on the types of genes discovered. WES is shown to be cost-effective and clinically useful. Sanger sequencing costs are about $1000 for the average gene. WES for very “genetically heterogeneous” disorders (i.e., caused by one of a potentially large number of genes), including familial amyotrophic lateral sclerosis (ALS), caused by 15 different genes; autosomal recessive deafness, caused by 39 genes; and Leigh’s encephalopathy, caused by 35 genes. Studies of multiple family members with the same phenotypes led to the discovery of mutation in known genes, thus expanding their known phenotypes: familial leukemia, germline p53 mutations found; fatal infantile encephalopathy, SLC19A3; autosomal dominant distal myopathy, tropomysin; two members of a consanguineous family with macrocephaly and epiphyseal dysplasia, KIF7; and two relatives with osteoporosis, CLCN7 (confirmed by finding cosegregation among four other family members).
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: osteopetrosis is a heterogeneous group of inherited disorders. The most severe early onset forms are all autosomal recessive. The three genes more commonly involved, TCIRG1, CLCN7 and OSTM1 contribute to the proper acidification of the osteoclast resorption lacuna, a prerequisite for optimum function of osteoclasts. TCIRG1 encodes an osteoclast-specific subunit (OC116) of the vacuolar proton pump (V-ATPase) and is responsible for roughly 50% of severe, early onset forms of AR osteopetrosis. CLCN7 and OSTM1 together form a molecular complex localised in late endosomes and lysosomes in the ruffled border of osteoclasts and are mutated in the neuropathic forms of AR osteopetrosis. More rarely, a severe early onset form of osteopetrosis can be secondary to mutations in the genes RANK (receptor activator of NF-kappa-B) or RANKL (ligand for RANK, or osteoclast differentiation factor, ODF), which are essential for osteoclastogenesis. Recently, recessive mutations in the gene SNX10, an interactor of V-ATPase, have been found in two consanguineous families.
The role of lysosomal ion channels in lysosome dysfunction
Published in Inhalation Toxicology, 2021
Rebekah L. Kendall, Andrij Holian
Individual ion channel activity has a significant effect on lysosomal homeostasis. As such, lysosomal ion channel activity is both a significant contributor to lysosome dysfunction and a valuable therapeutic target for diseases mediated by lysosomal dysfunction. Over the past decade, the patch-clamp technique has seen successful application to isolated lysosomes, allowing for the identification of lysosome-specific ion channels, leading to an increased understanding of ion channel activity in lysosome dysfunction and subsequent disease states. Each ion channel contributes in some way to maintaining lysosomal homeostasis but some have a more profound impact on lysosome function than others. Chloride ion (Cl−), maintained by the CLC7 H+/Cl− exchanger, has been reported to contribute to lysosomal acidification (Graves et al. 2008); however, lysosomes from CLC-7 KO mice appear to maintain normal pH in another study (Weinert et al. 2010). Confirmation of the necessity of Cl− transport through CLC-7 for lysosomal acidification is necessary to firmly establish this ion channel’s role in lysosome dysfunction. In contrast, the large Na+ and K+ gradients across the lysosomal membrane, and the Ca2+-signaling ability of the TRPML 1 channel, brings Na+, K+, and Ca2+ ion channels to the forefront of the discussion of ion channel activity in lysosomal dysfunction. To that end, this review will focus on the activities of the TRPML1, TPC, BK, and TMEM175 channels (Figure 2).