{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:13:59Z","timestamp":1790007239388,"version":"4.0.1"},"reference-count":34,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2008,4,23]],"date-time":"2008-04-23T00:00:00Z","timestamp":1208908800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2008,6]]},"abstract":"<jats:p>Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome, characterized by mandibular hypoplasia, acroosteolysis affecting distal phalanges and clavicles, delayed closure of the cranial sutures, atrophic skin, and lipodystrophy. Recently, mutations in lamin A\/C (<jats:italic>LMNA<\/jats:italic>) and zinc metalloprotease (<jats:italic>ZMPSTE24<\/jats:italic>), involved in post\u2010translational processing of prelamin A to mature lamin A, have been identified in MAD kindreds. We now report novel compound heterozygous mutations in exon 1 (c.121C&gt;T; p.Q41X) and exon 6 (c.743C&gt;T; p.P248L) in <jats:italic>ZMPSTE24 <\/jats:italic>in two Japanese sisters, 7\u2010 and 3\u2010year old, with severe MAD and characteristic facies and atrophic skin. The older sister had lipodystrophy affecting the chest and thighs but sparing abdomen. Their parents and a brother, who were healthy, had heterozygous mutations. The missense mutation, P248L, was not found in 100 normal subjects of Japanese origin. The mutant Q41X was inactive in a yeast halo assay; however, the mutant P248L retained near normal ZMPSTE24 activity. Immunoblots demonstrated accumulation of prelamin A in the patients\u2019 cell lysates from lymphoblasts. The lymphoblasts from the patients also revealed less intense staining for lamin A\/C on immunofluorescence. We conclude that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.<\/jats:p>","DOI":"10.1111\/j.1399-0004.2008.00992.x","type":"journal-article","created":{"date-parts":[[2009,1,23]],"date-time":"2009-01-23T10:19:28Z","timestamp":1232705968000},"page":"535-544","source":"Crossref","is-referenced-by-count":44,"title":["Severe mandibuloacral dysplasia caused by novel compound heterozygous <i>ZMPSTE24 <\/i>mutations in two Japanese 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