{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T12:03:55Z","timestamp":1791029035771,"version":"4.1.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2008,3,1]],"date-time":"2008-03-01T00:00:00Z","timestamp":1204329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We studied phenotypic and cellular aspects in a patient with a heterozygous mutation of the PLEKHM1 gene and obtained some indications regarding the role of the protein in bone cell function. Plekhm1 is involved in osteoclast endosomal vesicle acidification and TRACP exocytosis, contributing to events involved in osteoclast\u2013osteoblast cross-talk.<\/jats:p>\n               <jats:p>Introduction: The gene PLEKHM1 encodes a nonsecretory adaptor protein that localizes to endosomal vesicles. A highly truncated Plekhm1 protein was previously found in a patient with intermediate autosomal recessive osteopetrosis.<\/jats:p>\n               <jats:p>Materials and Methods: We describe a new heterozygous mutation in the PLEKHM1 gene in a patient presenting with low vertebral and femoral T-scores and areas of focal sclerosis. Clinical evaluation, mutational analysis, assessment of in vitro osteoclast morphology and activity, transfection studies, and evaluation of osteoclast\u2013osteoblast cross-talk were carried out.<\/jats:p>\n               <jats:p>Results: Direct DNA sequencing showed a heterozygous C to T substitution on cDNA position 2140 of the PLEKHM1 gene, predicted to lead to an R714C mutant protein. The mutation was not found in 104 control chromosomes. In vitro, patient's osteoclasts showed normal formation rate, morphology, number of nuclei, and actin rings but lower TRACP activity and higher endosomal pH than control osteoclasts. The patient had high serum PTH and TRACP, despite low TRACP activity in osteoclasts in vitro. HEK293 cells overexpressing either wildtype or Plekhm1-R714C showed no difference in localization of the variants, and co-transfection with a TRACP vector confirmed low TRACP activity in cells carrying the R714C mutation. RAW 264.7 osteoclast-like cells expressing the Plekhm1-R714C variant also showed low TRACP activity and reduced ability to acidify endosomal compartments compared with cells expressing the wildtype protein. Reduced intracellular TRACP was caused by increased protein secretion rather than reduced expression. TRACP-containing conditioned medium was able to increase osteoblast alkaline phosphatase, suggesting the focal osteosclerosis is a result of increased osteoclast\u2013osteoblast coupling.<\/jats:p>\n               <jats:p>Conclusions: We provide further evidence for a role of Plekhm-1 in osteoclasts by showing that a novel mutation in PLEKHM1 is associated with a complex bone phenotype of generalized osteopenia combined with \u201cfocal osteosclerosis.\u201d Our data suggest that the mutation affects endosomal acidification\/maturation and TRACP exocytosis, with implications for osteoclast\u2013osteoblast cross-talk.<\/jats:p>","DOI":"10.1359\/jbmr.071107","type":"journal-article","created":{"date-parts":[[2007,11,12]],"date-time":"2007-11-12T19:57:53Z","timestamp":1194897473000},"page":"380-391","source":"Crossref","is-referenced-by-count":77,"title":["A New Heterozygous Mutation (R714C) of the Osteopetrosis Gene, <i>Pleckstrin Homolog Domain Containing Family M (With Run Domain) Member 1 (PLEKHM1)<\/i>, Impairs Vesicular Acidification and Increases TRACP Secretion in Osteoclasts"],"prefix":"10.1093","volume":"23","author":[{"given":"Andrea","family":"Del Fattore","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachele","family":"Fornari","sequence":"additional","affiliation":[{"name":"Department of Medical Physiopathology, University \u201cLa Sapienza\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesbeth","family":"Van Wesenbeeck","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenna","family":"de Freitas","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Timmermans","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Biology and Histology, University of Antwerp, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Peruzzi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Cappariello","sequence":"additional","affiliation":[{"name":"Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Rucci","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Spera","sequence":"additional","affiliation":[{"name":"Department of Medical Physiopathology, University \u201cLa Sapienza\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miep H","family":"Helfrich","sequence":"additional","affiliation":[{"name":"Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim","family":"Van Hul","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Migliaccio","sequence":"additional","affiliation":[{"name":"Department of Medical Physiopathology, University \u201cLa Sapienza\u201d, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Teti","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020319460242900_bib1","first-page":"753","volume-title":"Connective Tissue and Its Heritable Disorders: Medical, Genetic, and Molecular Aspects","author":"Whyte","year":"2002","edition":"2nd ed"},{"key":"2024020319460242900_bib2","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/S0720-048X(01)00400-4","article-title":"Molecular and radiological diagnosis of sclerosing bone dysplasias","volume":"40","author":"Van Hul","year":"2001","journal-title":"Eur J 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