title: Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings.
abstract: 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 (LMNA) and zinc metalloprotease (ZMPSTE24), involved in post-translational 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>T; p.Q41X) and exon 6 (c.743C>T; p.P248L) in ZMPSTE24 in two Japanese sisters, 7- and 3-year 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' 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.
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Miyoshi
authors.forename: M
authors.initials: M
authors.lastname: Akagi
authors.forename: A K
authors.initials: AK
authors.lastname: Agarwal
authors.forename: N
authors.initials: N
authors.lastname: Namba
authors.forename: K
authors.initials: K
authors.lastname: Kato-Nishimura
authors.forename: I
authors.initials: I
authors.lastname: Mohri
authors.forename: M
authors.initials: M
authors.lastname: Yamagata
authors.forename: S
authors.initials: S
authors.lastname: Nakajima
authors.forename: S
authors.initials: S
authors.lastname: Mushiake
authors.forename: M
authors.initials: M
authors.lastname: Shima
authors.forename: R J
authors.initials: RJ
authors.lastname: Auchus
authors.forename: M
authors.initials: M
authors.lastname: Taniike
authors.forename: A
authors.initials: A
authors.lastname: Garg
authors.forename: K
authors.initials: K
authors.lastname: Ozono
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D044466:Asian People; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D034904:Lamin Type A; D008060:Lipodystrophy / Q000235:genetics; D008334:Mandible / Q000002:abnormalities*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics*; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D054876:Prenylation; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D035781:Siblings
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human