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. 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. Keywords 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...

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update

“…Missense mutations such as p.Trp340Arg or p.Asn265Ser lead to a reduced catalytic ZMPSTE24 activity. 13,27 All the reported cases of MAD-B phenotypes followed this pathophysiological rule. 22,23,25,27 An apparent exception to this general rule has been reported by Denecke et al 26 but is explained by a digenic mechanism involving both ZMPSTE24 and LMNA.…”

“…13,27 All the reported cases of MAD-B phenotypes followed this pathophysiological rule. 22,23,25,27 An apparent exception to this general rule has been reported by Denecke et al 26 but is explained by a digenic mechanism involving both ZMPSTE24 and LMNA. The case reported in this study was described as a HGPS patient but, according to molecular findings and our current knowledge, it should be classified as a severe MAD-B.…”

“…Other mutations were found in additional cases of RD [15][16][17][18][19][20][21] and progeroid syndromes phenotypically overlapping with MAD and HGPS that can be nosologically classified as MAD-B, given the common molecular basis, involving ZMPSTE24 deficiency. 13,[22][23][24][25][26][27][28] RD, MAD-B and HGPS share a common pathophysiological mechanism based on the abnormal accumulation of a wild type or modified lamin A precursors.…”

Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation

“…9,32-34 These ZMPSTE24 mutations result not only in the presence of traces of prelamin A but also that of mature lamin A 33 because of partial residual ZMPSTE24 activity. 9,32,33 All these reports strongly suggest a link between phenotype severity, prelamin A accumulation levels and ZMPSTE24 residual activity. Complete prelamin A accumulation with null ZMPSTE24 enzyme activity can be correlated to the most severe progeroid syndrome, RD; null ZMPSTE24 activity rescued by a heterozygous LMNA null mutation causes a severe, HGPS-like, MADB phenotype, whereas partial accumulation of prelamin A with reduced ZMPSTE24 enzyme activity is associated with milder MADB phenotypes.…”

“…Such calcifications have been reported in four ZMPSTE24-related MADB cases, two of them requiring surgical removal, 9,36 but not in the two others. 33 Similarly, a homozygous LMNA mutation c.1718C4T leading to the missense substitution p.Ser573Leu has been reported to result in progeroid features associated with arthropathy and tendinous calcinosis 37 without any prelamin A accumulation. Furthermore, renal artery calcifications and chronic kidney disease were responsible for pharmacoresistant high blood pressure as observed in ZMPSTE24-related MADB.…”