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. Mutations in LMNA gene are also associated with other progeroid syndromes such as Hutchinson-Gilford progeria syndrome(HGPS), restrictive dermopathy (RD), progeriaassociated arthropathy, and atypical progeroid syndrome (also referred to as atypical Werner's syndrome) (13-16). Mutations in ZMPSTE24 gene are also associated with RD (17,18). There are many overlapping features among patients with MAD, HGPS, RD and atypical progeroid syndrome, although each presents with some unique phenotypic features. So far, 21 MAD patients have been reported to have LMNA mutations (6-10), but only 3 MAD patients have been reported with ZMPSTE24 mutations (11,19,20). Here, we report two Japanese siblings with MAD resulting from novel compound heterozygous mutations in ZMPSTE24.
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Materials and methodsThe studies were approved by the Institutional Review Boards of the Osaka University Hospital and the University of Texas Southwestern Medical Center at Dallas. Each participant or their legal guardian gave a written informed consent for all studies and photographs.
Mutational analysis of the LMNA and ZMPSTE24 genesGenomic DNA was isolated from the subjects' peripheral whole blood cells using Dr. GenTLE (Takara Bio, Otsu, Shiga, Japan) according to the manufacturer's instructions. Direct sequencing of the entire coding region and the flanking exon-intron boundaries of the LMNA and ZMPSTE24 was first conducted in the proband, and the mutations were later confirmed in the younger sister. The primer sets that amplify each exon of LMNA and ZMPSTE24 genes were designed from published sequence information and exons were amplified by polymerase cha...
