| *606480 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ZINC METALLOPROTEINASE STE24; ZMPSTE24 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| STE24, S. CEREVISIAE, HOMOLOG OF FACE1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: ZMPSTE24 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 1p34.2 Genomic coordinates (GRCh37): 1:40,723,732 - 40,759,855 (from NCBI) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The ZMPSTE24 gene encodes a zinc metalloproteinase involved in the processing of farnesylated proteins (Freije et al., 1999). The significance of ZMPSTE24 in human disease stems from its role as an enzyme necessary for the correct processing and maturation of lamin A (LMNA; 150330), an intermediate filament component of the nuclear envelope (Moulson et al., 2005). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| By EST database searching with the yeast Ste24 sequence, Tam et al. (1998) identified a homologous human EST which they used to isolate a human STE24 cDNA, symbolized ZMPSTE24, from a B-cell library. Freije et al. (1999) independently identified ZMPSTE24, which they called FACE1, by EST database searching for sequences with similarity to yeast AFC1, a protein essential for the proteolytic processing of yeast farnesylated/prenylated proteins. ZMPSTE24 encodes a deduced 475-amino acid protein that shares 36% sequence identity with S. cerevisiae Ste24. ZMPSTE24 contains a characteristic HEXXH zinc metalloprotease motif, several transmembrane regions, and regions I, II, and III that are conserved among a subfamily of zinc metalloproteases. Freije et al. (1999) identified regions of high hydrophobicity, consistent with ZMPSTE24 being a polytopic integral membrane protein and concluded that it is a metalloprotease potentially involved in the processing of farnesylated proteins in human tissues. Using an in vitro translation product for SDS-PAGE analysis, Freije et al. (1999) detected a 55-kD ZMPSTE24 protein. By Northern blot analysis, they detected ubiquitous expression of a 3.5-kb ZMPSTE24 transcript. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| By radiation hybrid analysis and FISH, Freije et al. (1999) mapped the ZMPSTE24 gene to chromosome 1p34. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tam et al. (1998) found that Ste24 in S. cerevisiae participates in both amino- and carboxy-terminal processing steps during maturation of the mating pheromone a-factor. They demonstrated that human ZMPSTE24 can complement the mating defect of the yeast Ste24/Rce1 double mutant strain. They concluded that, like yeast Ste24, human ZMPSTE24 can mediate multiple types of proteolytic events. Human immunodeficiency virus (HIV)-1 (see 609423) protease inhibitors (PIs) targeting the viral aspartyl protease are a cornerstone of treatment for HIV infection and disease, but they are associated with lipodystrophy and other side effects. Coffinier et al. (2007) found that treatment of human and mouse fibroblasts with HIV-PIs caused an accumulation of prelamin A (150330). The prelamin A in HIV-PI-treated fibroblasts migrated more rapidly than nonfarnesylated prelamin A, comigrating with the farnesylated form found in ZMPSTE24-deficient fibroblasts. HIV-PI-treated heterozygous ZMPSTE24 fibroblasts exhibited an exaggerated accumulation of farnesyl-prelamin A. Western blot and enzymatic analysis showed that HIV-PIs inhibited ZMPSTE24 activity and endoproteolytic processing of a GFP-prelamin A fusion protein, but they did not affect farnesylation of HDJ2 (DNAJA1; 602837) or activity of farnesyltransferase (see 134635), ICMT (605851), and RCE1 (605385) in vitro. Coffinier et al. (2007) concluded that HIV-PIs inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A, possibly explaining HIV-PI side effects. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mandibuloacral Dysplasia With Type B Lipodystrophy Mandibuloacral dysplasia is a rare, genetically and phenotypically heterogeneous, autosomal recessive disorder characterized by skeletal abnormalities including hypoplasia of the mandible and clavicles, acroosteolysis, cutaneous atrophy, and lipodystrophy (608612). Based on phenotypic and biochemical similarities with Zmpste24 -/- mice (Pendas et al., 2002), Agarwal et al. (2003) considered ZMPSTE24 as a candidate gene for patients with MAD who carried no mutations in the LMNA (150330) gene. The authors demonstrated compound heterozygosity for 2 mutations in the ZMPSTE24 gene (606480.0001-606480.0002) in 1 of 4 MAD patients. ZMPSTE24 is involved in posttranslational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A to form mature lamin A. Based on the phenotype of Zmpste24 -/- mice and complementation studies in mutant yeast strains, the authors concluded that mutations in ZMPSTE24 may cause MAD by affecting prelamin A processing. Lethal Restrictive Dermopathy In 7 patients with restrictive dermopathy (275210), a lethal genodermatosis in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence, Navarro et al. (2004) identified a heterozygous 1-bp insertion resulting in a premature stop codon in the ZMPSTE24 gene (1085dupT; 606480.0001). This gene encodes a metalloproteinase specifically involved in the posttranslational processing of lamin A precursor. In all patients carrying a ZMPSTE24 mutation, loss of expression of lamin A as well as abnormal patterns of nuclear sizes and shapes and mislocalization of lamin-associated proteins was seen. Two of 9 fetuses with restrictive dermopathy carried heterozygous splicing mutations in the LMNA gene, resulting in the complete or partial loss of exon 11 (150330.0036 and 150330.0022, respectively). Navarro et al. (2004) concluded that a common pathogenetic pathway, involving defects of the nuclear lamina and matrix, is involved in restrictive dermopathy. Navarro et al. (2005) described 7 previously reported patients and 3 new patients with restrictive dermopathy who were homozygous or compound heterozygous for ZMPSTE24 mutations. In all cases there was complete absence of both ZMPSTE24 and mature lamin A, associated with prelamin A accumulation. The authors concluded that restrictive dermopathy is either a primary or a secondary laminopathy, caused by dominant de novo LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations. The accumulation of truncated or normal length prelamin A is, therefore, a shared pathophysiologic feature in recessive and dominant restrictive dermopathy. Moulson et al. (2005) identified homozygous or compound heterozygous mutations in the ZMPSTE24 gene (606480.0001; 606480.0007; 606480.0008) in patients with lethal restrictive dermopathy. All the mutations resulted in premature truncation and lack of a functional protein. Cultured cells and tissue from affected individuals showed accumulation of unprocessed toxic lamin A and aggregates of lamin A in nuclei, suggesting that the disorder results from defective processing of lamin A. In a female infant with lethal restrictive dermopathy, who was negative for mutation in LMNA, Chen et al. (2009) identified homozygosity for a nonsense mutation in the ZMPSTE24 gene (606480.0006). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Denecke et al. (2006) described a patient considered to have Hutchinson-Gilford progeria syndrome (HGPS; 176670), which is usually caused by a heterozygous mutation in LMNA gene (150330), which codes for the nuclear lamina protein lamin A, and was found to have a combined defect of a homozygous loss-of-function mutation in the ZMPSTE24 gene and a heterozygous mutation in the LMNA gene that resulted in a C-terminal elongation of the final lamin A. Whereas a loss-of-function mutation of ZMPSTE24 normally results in lethal restrictive dermatopathy, the truncation of LMNA seems to have been a salvage alteration alleviating the clinical picture to the HGPS phenotype in this patient. The mutations in this patient indicated that farnesylated prelamin A is the deleterious agent leading to the HGPS phenotype, thus giving further insight into the pathophysiology of that disorder. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pendas et al. (2002) reported that disruption of the Zmpste24 gene caused severe growth retardation and premature death in homozygous-null mice. Histopathologic analysis of the mutant mice showed several abnormalities, including dilated cardiomyopathy, muscular dystrophy, and lipodystrophy. These alterations were similar to those developed by mice deficient in A-lamin (LMNA; 150330), a major component of the nuclear lamina, and phenocopied most defects observed in humans with diverse congenital laminopathies, such as autosomal dominant Emery-Dreifuss muscular dystrophy (181350), autosomal dominant dilated cardiomyopathy with conduction defects (115200), and familial partial lipodystrophy of the Dunnigan type (151660). In agreement with this finding, Zmpste24-null mice are defective in the proteolytic processing of prelamin A. This deficiency in prelamin A maturation leads to the generation of abnormalities in nuclear architecture that probably underlie the many phenotypes observed in both mice and humans with mutations in the lamin A gene. These results indicated that prelamin A is a specific substrate for Zmpste24 and demonstrated the usefulness of genetic approaches for identifying the in vivo substrates of proteolytic enzymes. Bergo et al. (2002) studied Zmpste24 -/- mice and showed that they gained weight slowly, appeared malnourished, and exhibited progressive hair loss. A more striking pathologic phenotype was multiple spontaneous bone fractures, akin to those occurring in mouse models of osteogenesis imperfecta. Cortical and trabecular bone volumes were significantly reduced. They also manifested muscle weakness in the limbs, resembling mice lacking the farnesylated CAAX protein prelamin A. Prelamin A processing was defective both in fibroblasts lacking Zmpste24 and in fibroblasts lacking the CAAX carboxylmethyltransferase Icmt (605851), but was normal in fibroblasts lacking the CAAX endoprotease Rce1 (605385). Weakness in the null mice could be reasonably ascribed to a defective processing of prelamin A, but the brittle bone phenotype suggested a broader role for Zmpste24 in mammalian biology. In Zmpste24-deficient mouse embryonic fibroblasts (MEFs), Liu et al. (2005) observed increased DNA damage, chromosomal aberrations, and sensitivity to DNA-damaging agents. Recruitment of p53-binding protein-1 (TP53BP1; 605230) and Rad51 (179617) to sites of DNA lesion was impaired in Zmpste24-null MEFs and in Hutchinson-Gilford progeria syndrome (176670) fibroblasts, resulting in a delayed checkpoint response and defective DNA repair; wildtype MEFs ectopically expressing unprocessible prelamin A showed similar defects in checkpoint response and DNA repair. Liu et al. (2005) concluded that unprocessed prelamin A and truncated lamin A act in a dominant-negative fashion to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging. Varela et al. (2005) analyzed the transcriptional alterations occurring in tissues from Zmpste24-deficient mice and demonstrated that Zmpste24 deficiency elicits a stress signaling pathway that is evidenced by a marked upregulation of p53 (191170) target genes, and accompanied by a senescence phenotype at the cellular level and accelerated aging at the organismal level. These phenotypes are largely rescued in Zmpste24-null/Lmna (150330) heterozygous mice and partially reversed in Zmpste24-null/p53-null mice. Varela et al. (2005) concluded that their findings provided evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin-A accumulation, and supported the concept that hyperactivation of the tumor suppressor p53 may cause accelerated aging. In progeria, the accumulation of farnesyl-prelamin A disrupts the structural scaffolding for the cell nucleus, leading to misshapen nuclei. Previous studies (e.g., Mallampalli et al., 2005) had shown that farnesyltransferase inhibitors (FTIs) reverse this cellular abnormality. Fong et al. (2006) tested the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria. The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. Fong et al. (2006) concluded that FTIs may have beneficial effects in humans with progeria. Varela et al. (2008) found that combined treatment of Zmpste24-null mice with statins and aminobisphosphonates resulted in amelioration of the aging-like phenotype, with increased amounts of subcutaneous fat, reduced kyphosis, alopecia, and osteoporosis, and extended life span. The mechanism of treatment involved the inhibition of farnesyl pyrophosphate synthesis and prevention of cross-prenylation of prelamin A. This resulted in improved nuclear morphology and decreased accumulation of prelamin A. This treatment failed to extend the life span of Lmna-null mice. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 MANDIBULOACRAL DYSPLASIA WITH TYPE B LIPODYSTROPHY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| RESTRICTIVE DERMOPATHY, LETHAL, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ZMPSTE24, 1-BP DUP, 1085T | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Belgian woman with mandibuloacral dysplasia, progeroid appearance, and generalized lipodystrophy (608612), Agarwal et al. (2003) identified compound heterozygosity for a 1-bp duplication (1085dupT) in exon 9 of the ZMPSTE24 gene, resulting in a frameshift and a truncated protein (phe361fsX379), and a missense mutation (606480.0002). Neither mutation was found among 100 control subjects. Navarro et al. (2004) identified a heterozygous 1085dupT mutation 7 unrelated infants with lethal restrictive dermopathy (275210). The mutation was predicted to result in a frameshift and a premature stop codon 18 codons downstream. Loss of expression of lamin A (LMNA; 150330), abnormal patterns of nuclear sizes and shapes, and mislocalization of lamin-associated proteins was seen in fibroblasts from these patients. Moulson et al. (2005) hypothesized that the patients reported by Navarro et al. (2004) with heterozygous mutations actually had a second pathogenic mutation in the ZMPSTE24 gene that was not detected. Moulson et al. (2005) identified a homozygous 1085dupT mutation in a Dutch patient and in a American patient of German origin, both with restrictive dermopathy. The Dutch patient was born of consanguineous parents. Fibroblasts derived from a patient who was homozygous for the mutation showed that LMNA was distributed in clusters in the nucleus, which was different from the uniform distribution of LMNA in nuclei of control fibroblasts. These findings indicated that the disorder results from a specific defect in LMNA processing. Another unrelated Dutch patient with restrictive dermopathy disorder was compound heterozygous for 2 mutations: 1085dupT and 591dupT (606480.0008). Li (2010) identified a homozygous 1085dupT mutation in an infant girl with restrictive dermopathy. She was born of Mexican Mennonite parents who had immigrated to Canada. The mother reported several neonatal deaths in her family. Li (2010) postulated that since this family was of Mennonite descent, it may represent a founder mutation in this group. However, Miner (2010) noted that Moulson et al. (2005) had previously identified a different truncating mutation in the ZMPSTE24 gene (54dupT; 606480.0007) as causing restrictive dermopathy in 2 related Mennonite families from Pennsylvania, suggesting allelic heterogeneity even within this isolated population. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0002 MANDIBULOACRAL DYSPLASIA WITH TYPE B LIPODYSTROPHY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ZMPSTE24, TRP340ARG [dbSNP:rs121908093] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Belgian woman with mandibuloacral dysplasia with type B lipodystrophy (608612), Agarwal et al. (2003) found a 1018T-to-C transition in exon 8 of the ZMPSTE24 gene, resulting in a trp340-to-arg (W340R) amino acid substitution. This mutation was found in compound heterozygosity with a frameshift mutation (606480.0001). The unaffected parents and 2 sibs of the proband each were heterozygous for 1 of the mutations. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0003 REMOVED FROM DATABASE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0004 MANDIBULOACRAL DYSPLASIA WITH TYPE B LIPODYSTROPHY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ZMPSTE24, GLN41TER [dbSNP:rs121908094] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 Japanese sisters with mandibuloacral dysplasia with type B lipodystrophy (608612), Miyoshi et al. (2008) identified compound heterozygosity for 2 mutations in the ZMPSTE24 gene: a 121C-T transition in exon 1, resulting in a gln41-to-ter (Q41X) substitution, and a 743C-T transition, resulting in a pro248-to-leu (P248L; 606480.0005) substitution in a conserved residue adjacent to the sixth membrane-spanning domain. Neither mutation was found in 200 Japanese control chromosomes. In vitro functional studies in yeast showed that the Q41X-mutant protein was inactive, but the P248L-mutant protein was similar to wildtype. However, patient lymphocytes showed accumulation of prelamin A, indicating ZMPSTE24 deficiency. The patients had a severe form of the disorder with clinical features apparent before age 2 years. The findings indicated that haploinsufficiency combined with even a minor loss of enzyme activity in the other allele is sufficient to cause the clinical features of MAD. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0005 MANDIBULOACRAL DYSPLASIA WITH TYPE B LIPODYSTROPHY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ZMPSTE24, PRO248LEU [dbSNP:rs121908095] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 606480.0004 and Miyoshi et al. (2008). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0006 RESTRICTIVE DERMOPATHY, LETHAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ZMPSTE24, GLU239TER | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a female infant with lethal restrictive dermopathy (275210), born to aboriginal Taiwanese parents from the same tribe but not known to be consanguineous, Chen et al. (2009) identified homozygosity for a 715G-T transversion in exon 6 of the ZMPSTE24 gene, resulting in a glu239-to-ter (E239X) substitution. The unaffected parents and both grandmothers were heterozygous for the ZMPSTE24 mutation; an unaffected older sister did not inherit the mutation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0007 RESTRICTIVE DERMOPATHY, LETHAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ZMPSTE24, 1-BP DUP, 54T | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Mennonite infant with restrictive dermopathy (275210), Moulson et al. (2005) identified a homozygous 1-bp duplication (54dupT) in exon 1 of the ZMPSTE24 gene, predicted to result in a frameshift and premature truncation. The parents were both heterozygous for the mutation and had 3 deceased affected children, but DNA was only available from 1 affected child. Two additional affected sibs were reported in a related family, and the parents and an unaffected child were heterozygous for the mutation, but DNA was not available from the 2 deceased affected children. The 2 families were part of an extended Mennonite kindred, as the fathers were brothers and the mothers were first cousins of each other. Moulson et al. (2005) noted that the Lowry et al. (1985) had reported restrictive dermopathy in a Mennonite kindred, and suggested that the 54dupT mutation may segregate in this population. Li (2010) reported a different homozygous mutation (1085dupT; 606480.0001) in a Mennonite patient with restrictive dermopathy, suggesting allelic heterogeneity in this population. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0008 RESTRICTIVE DERMOPATHY, LETHAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ZMPSTE24, 1-BP DUP, 591T | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Guatemalan infant, born of consanguineous parents, with restrictive dermopathy (275210), Moulson et al. (2005) identified a homozygous 1-bp duplication (591dupT) in exon 5 of the ZMPSTE24 gene, predicted to result in a frameshift and premature truncation. The parents were both heterozygous for the mutation. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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