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

Abstract

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.

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

“…Patients' death results in most cases from respiratory failure [169,170]. Most patients affected with RD carry homozygous or compound heterozygous null mutations in ZMPSTE24 [171] while a very small subset of RD cases are associated to splicing mutations in LMNA with similar pathophysiological consequences as compared to HGPS [144]. These observations raised the concept of prelamin A-deficient processing associated syndromes, being a clinical continuum of apparently heterogeneous disorders, whose the disease evolution and severity depends the dose of accumulated farnesylated mis-processed prelamin A [144,171,172].…”

Teledermatology diagnosis of the first Italian patient affected with restrictive dermopathy due to ZMPSTE24 homozygous mutation

“…4,5 The ZMPSTE24 p.Leu362PhefsTer19 is a common frameshift mutation first described in French and Dutch patients, 1 and then in individuals of different geographic origin. 4,6,7 It represents a mutational hotspot due to homopolymeric thymine sequence instability. 4 It is associated with an early lethal phenotype, as in our patient, who is the first case reported in Italy.…”

Progeroid syndrome patients with ZMPSTE24 deficiency could benefit when treated with rapamycin and dimethylsulfoxide

“…Those mutants with no measurable protease activity are associated with RD and those that are partially active result in MAD (Barrowman et al 2012b). Several new mutations in ZMPSTE24 have recently been reported in MADB or RD (Navarro et al 2014; Wang et al 2016). A heterozygous ZMPSTE24 mutation is also shown to be associated with severe metabolic syndrome, abnormal fat accumulation, and dilated cardiomyopathy (Galant et al 2016).…”