A case of restrictive dermopathy with complete chorioamniotic membrane separation caused by a novel homozygous nonsense mutation in the <i>ZMPSTE24</i> gene

Chen, Ming; Kuo, Hsiang-Hsu; Huang, Yongjun; Ke, Yu-Yuan; Chang, Shun‐Ping; Chen, Chih‐Ping; Lee, Dong Hoon; Lee, Meng-Luen; Lee, Mei‐Hui; Chen, Tze-Ho; Chen, Chia‐Hsiang; Lin, Hui-Mei; Liu, Chin‐San; Ma, Gwo‐Chin

doi:10.1002/ajmg.a.32768

Cited by 15 publications

(14 citation statements)

References 11 publications

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“…Apart from one, 24 the 23 patients with typical RD features had either homozygous or compound heterozygous null mutations (nonsense, insertions or deletions) 10,11,17,[25][26][27][28][29][30] or very large in-frame deletions sometimes resulting from splice site mutations 10,11,16 in the ZMPSTE24 gene. Moreover, all RD-related mutations lead to a complete absence of the ZMPSTE24 protein or to null activity, consequently causing the accumulation of prelamin A and an absence of mature lamin A.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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Mutation in ZMPSTE24 gene, encoding a major metalloprotease, leads to defective prelamin A processing and causes type B mandibuloacral dysplasia, as well as the lethal neonatal restrictive dermopathy syndrome. Phenotype severity is correlated with the residual enzyme activity of ZMPSTE24 and accumulation of prelamin A. We had previously demonstrated that a complete loss of function in ZMPSTE24 was lethal in the neonatal period, whereas compound heterozygous mutations including one PTC and one missense mutation were associated with type B mandibuloacral dysplasia. In this study, we report a 30-year longitudinal clinical survey of a patient harboring a novel severe and complex phenotype, combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion. A unique homozygous missense ZMPSTE24 mutation (c.281T4C, p.Leu94Pro) was identified and predicted to produce two possible ZMPSTE24 conformations, leading to a partial loss of function. Western blot analysis revealed a major reduction of ZMPSTE24, together with the presence of unprocessed prelamin A and decreased levels of lamin A, in the patient's primary skin fibroblasts. These cells exhibited significant reductions in lifespan associated with major abnormalities of the nuclear shape and structure. This is the first report of MAD presenting with confirmed myopathic abnormalities associated with ZMPSTE24 defects, extending the clinical spectrum of ZMPSTE24 gene mutations. Moreover, our results suggest that defective prelamin A processing affects muscle regeneration and development, thus providing new insights into the disease mechanism of prelamin A-defective associated syndromes in general. Keywords: ZMPSTE24; mandibuloacral dysplasia; congenital myopathy; prelamin A; secondary laminopathies INTRODUCTION ZMPSTE24 (also known as FACE-1) encodes a ubiquitously expressed zinc metalloprotease. Prelamin A, the lamin A precursor, is the only known substrate of ZMPSTE24 in mammals. 1 ZMPSTE24 is involved in post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A to form mature lamin A. 2 Prelamin A is initially farnesylated on the last cysteine within the prenylation 'CaaX' motif at the C-terminus end of the protein by a farnesyltransferase. 3 Thereafter, ZMPSTE24 or RCE1 4 removes the last three residues 'aaX' , before a carboxy-methyl group is added by the methyl transferase ICMT on the last remaining cysteine. 5 Finally, a second cleavage is specifically carried out by ZMPSTE24, removing the last 15 amino acids. 6 The product of this post-translational maturation pathway, mature lamin A, is located both at the nuclear lamina and the nucleoplasm. A-type lamins A and C are expressed in all vertebrate differentiated cells, and are translated from alternatively spliced transcripts of the LMNA gene. After post-translational modifications,

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Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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“…On the opposite, in typical MAD-B, lipodystrophy is generalized, an earlier age of onset is observed (often during the first year of life) and the median age of death is 30 years. 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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.

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“…Restrictive dermopathy is caused by mutations in LMNA or ZMPSTE24 (38, 201, 212, 213, 289). ZMPSTE24 is a metalloproteinase that cleaves the immature, farnesylated form of lamin A to create the mature, unfarnesylated form of lamin A.…”

Section: Nuclear Envelopathiesmentioning

confidence: 99%

“…Mutations in LMNA causing restrictive dermopathy block the processing of prelamin A to the mature form of lamin A (213). Mutations in ZMPSTE24 result in the accumulation of prelamin A (38, 201, 212, 289), due to the inability of ZMPSTE24 to cleave prelamin A. A few patients carrying mutations in ZMPSTE24 lacked lamin A expression, while others maintained lamin A expression.…”

Section: Nuclear Envelopathiesmentioning

confidence: 99%

Diseases of the Nucleoskeleton

Holaska

2016

Comprehensive Physiology

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The nucleus is separated from the cytosol by the nuclear envelope, which is a double lipid bilayer composed of the outer nuclear membrane and the inner nuclear membrane. The intermediate filament proteins lamin A, lamin B, and lamin C form a network underlying the inner nuclear membrane. This proteinaceous network provides the nucleus with its strength, rigidity, and elasticity. Positioned within the inner nuclear membrane are more than 150 inner nuclear membrane proteins, many of which interact directly with lamins and require lamins for their inner nuclear membrane localization. Inner nuclear membrane proteins and the nuclear lamins define the nuclear lamina. These inner nuclear membrane proteins have tissue-specific expression and diverse functions including regulating cytoskeletal organization, nuclear architecture, cell cycle dynamics, and genomic organization. Loss or mutations in lamins and inner nuclear membrane proteins cause a wide spectrum of diseases. Here, I will review the functions of the well-studied nuclear lamina proteins and the diseases associated with loss or mutations in these proteins. © 2016 American Physiological Society.

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A case of restrictive dermopathy with complete chorioamniotic membrane separation caused by a novel homozygous nonsense mutation in the ZMPSTE24 gene

Cited by 15 publications

References 11 publications

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

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

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

Diseases of the Nucleoskeleton

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