Homozygous and Compound Heterozygous Mutations in ZMPSTE24 Cause the Laminopathy Restrictive Dermopathy

Abstract

Restrictive dermopathy (RD) is a lethal human genetic disorder characterized by very tight, thin, easily eroded skin, rocker bottom feet, and joint contractures. This disease was recently reported to be associated with a single heterozygous mutation in ZMPSTE24 and hypothesized to be a digenic disorder (Navarro et al, Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet 13:2493-2503, 2004). ZMPSTE24 encodes an enzyme necessary for the correct processing and maturation of lamin A, an intermediate filament component of the nuclear envelope. Here we present four unrelated patients with homozygous mutations in ZMPSTE24 and a fifth patient with compound heterozygous mutations in ZMPSTE24. Two of the three different mutations we found are novel, and all are single base insertions that result in messenger RNA frameshifts. As a consequence of the presumed lack of ZMPSTE24 activity, prelamin A, the unprocessed toxic form of lamin A, was detected in the nuclei of both cultured cells and tissue from RD patients, but not in control nuclei. Abnormally aggregated lamin A/C was also observed. These results indicate that RD is an autosomal recessive laminopathy caused by inactivating ZMPSTE24 mutations that result in defective processing and nuclear accumulation of prelamin A.

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

“…In family 2 (Figure 1Ab), the child of a consanguineous Turkish couple, presented a novel homozygous deletion of two nucleotides in exon 2, c.209_210delAT. In a third family (Figure 1Ac), the compound heterozygous mutations c.54dupT, previously described in Moulson et al 14 and a novel nonsense mutation located in exon 7 (c.826C4T) were observed. A further novel homozygous mutation, c.1105C4T located in exon 9, causing a stop gain, led to RD in a consanguineous German family 4 ( Figure 1Ad).…”

“…However, no blebs or herniations lacking lamin B, which are usually observed in ZMPSTE24-deficient cells, were found. 1,3,14,31 The nuclear abnormalities observed in this patient could be due to mutations of lamin A partners or other nuclear proteins. Another child of a consanguineous couple was affected with a complex progeroid phenotype, including neonatal insulin resistance, lipodystrophy, facial dysmorphism as well as growth and psychomotor retardation.…”

“…This mutation was previously identified as the most frequent one involved in RD. 3,14 Based on molecular genetics findings, seven families asked for prenatal diagnosis of RD after genetic counseling. As a result, two homozygous wild type, six heterozygous and two homozygous or compound heterozygous RD fetuses were identified.…”

“…10 After the identification of the main genetic cause of HGPS as a de novo LMNA mutation (c.1824C4T, Gly608Gly) affecting splicing and prelamin A maturation, 11,12 mutations in ZMPSTE24 were then identified in patients affected by severe Mandibulo-acral dysplasia associated with B-type lipodystrophy (MAD-B), 13 and later in RD. 1,3,14 Clinically, MAD is characterized by skeletal abnormalities including hypoplasia of the mandible and clavicles, acro-osteolysis of distal phalanges, cutaneous atrophy and lipodystrophy. MAD-A, linked to LMNA mutations, is associated with a partial lipodystrophy of the extremities.…”

Mouse models of the laminopathies

“…Recessive mutations resulting in complete absence of ZMPSTE24 cause restrictive dermopathy, which is characterized by intrauterine growth retardation, rigid or tight skin with prominent superficial vessels, defects in bone mineralization, dysplastic clavicles, and early postnatal death [72,73]. Hypomorphic ZMPSTE24 alleles can lead to the accumulation of some unprocessed prelamin A in addition to mature lamin A, indicating residual activity of the mutated ZMPSTE24 protein.…”