Article

Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia

Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
Human Molecular Genetics (Impact Factor: 6.39). 09/2003; 12(16):1995-2001. DOI: 10.1093/hmg/ddg213
Source: PubMed

ABSTRACT

Mandibuloacral dysplasia (MAD; OMIM 248370) is a rare, genetically and phenotypically heterogeneous, autosomal recessive disorder characterized by skeletal abnormalities including hypoplasia of the mandible and clavicles, acro-osteolysis, cutaneous atrophy and lipodystrophy. A homozygous missense mutation, Arg527His, in the LMNA gene which encodes nuclear lamina proteins lamins A and C has been reported in patients with MAD and partial lipodystrophy. We studied four patients with MAD who had no mutations in the LMNA gene. We now show compound heterozygous mutations, Phe361fsX379 and Trp340Arg, in the zinc metalloproteinase (ZMPSTE24) gene in one of the four patients who had severe MAD associated with progeroid appearance and generalized lipodystrophy. ZMPSTE24 is involved in post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A in two steps to form mature lamin A. Deficiency of Zmpste24 in mice causes accumulation of prelamin A and phenotypic features similar to MAD. The yeast homolog, Ste24, has a parallel role in processing of prenylated mating pheromone a-factor. Since human ZMPSTE24 can also process a-factor when expressed in yeast, we assessed the functional significance of the two ZMPSTE24 mutations in the yeast to complement the mating defect of the haploid MATa yeast lacking STE24 and Ras-converting enzyme 1 (RCE1; another prenylprotein-specific endoprotease) genes. The ZMPSTE24 mutant construct, Phe361fsX379, was inactive in complementing the yeast a-factor but the mutant, Trp340Arg, was partially active compared to the wild type ZMPSTE24 construct. We conclude that mutations in ZMPSTE24 may cause MAD by affecting prelamin A processing.

    • "These findings prompted us to specifically analyze the POLD1 gene in patients referred to the International Registry of Werner Syndrome (http://www.pathology. washington.edu/research/werner/registry/registry.html) for whom we had previously excluded WRN and LMNA mutations as well as mutations in BANF1 and ZMPSTE24, two genes that were reported to be also involved in segmental progeroid disorders [Agarwal et al., 2003; Puente et al., 2011]. "
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    ABSTRACT: Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner Syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few non-classical cases of WS, another 10-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: Mandibular hypoplasia, Deafness, Progeroid features (MDP) syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with Werner Syndrome. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably under-diagnosed segmental progeroid syndrome. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Human Mutation
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    • "Lipodystrophy, familial partial, type 2 PLIN1 Perilipin 1 613877; 170290 [57] Lipodystrophy, familial partial, type 4 PPARG Peroxisome proliferator activated receptor gamma 601487; 604367 [64] Lipodystrophy, familial partial type 3 PTRF RNA polymerase 1 and transcript release factor 603198; 613327 [63] Lipodystrophy, congenital generalized, type 4 ZMPSTE24 Zinc metalloproteinase STE24 606480; 608612 [5] Mandibuloacral dysplasia with lipodystrophy 2) Inherited insulin resistance and obesity syndromes: elevated triglycerides and depressed HDL cholesterol INSR Insulin receptor 246200; 262190; 147670 [87] [137] Group of related disorders, including Leprechaunism (Donahue syndrome), Rabson–Mendenhall syndrome and Type A insulin resistance LEP Leptin 164160 [123] 3) Maturity-onset diabetes of the young (MODY) syndromes HNF1A Hepatic nuclear factor 1-alpha 142410; 600496 [49] [7] MODY type 3; some individuals have metabolic syndrome with elevated triglyceride levels HNF4A Hepatic nuclear factor 4-alpha 600281; 600496 [181] MODY type 4; some individuals have low triglyceride levels 4) Monogenic disorders of bile acid metabolism and cholesterol biosynthesis SLC10A2 Ileal sodium bile salt transporter 601295; 613291 [138] Primary bile acid malabsorption, with congenital diarrhea, steatorrhea, and reduced plasma cholesterol DHCR7 Sterol delta-7 reductase 270400; 602858 [136] Children with Smith–Lemli–Opitz syndrome have reduced levels of total cholesterol 5) Monogenic multisystem disorders with incidental dyslipidemia FBN1 Fibrillin 1 134797 [61] Unusual single family with Marfan syndrome, progeroid features and hypertriglyceridemia G6PC Glucose-6-phosphatase 613742; 232200 [106] Type 1a glycogen storage disease (von Geirke); hypertriglyceridemia can be severe GK Glycerol kinase 300474; 307030 [198] Glycerol kinase deficiency causes factitious hypertriglyceridemia JAG1 Jagged 1 118450; 601920 [100] Children with Alagille syndrome show increased levels of total and LDL cholesterol and triglycerides SMPD1 Sphingomyelin phosphodiesterase 1 607608; [102] Atypical single family with Niemann Pick disease type B and very low HDL cholesterol TNFRSF6 Tumor necrosis factor receptor superfamily member 6 601859; 134637 [9] Atypical single family with autoimmune lymphoproliferative syndrome, splenomegaly, cytopenia and hypertriglyceridemia Table 3 Mouse studies 1) into the molecular genetics of human dyslipidemia; 2) into genomic regions/genes that control plasma lipid levels in mice, and studies that 3) happened to reveal dyslipidemic phenotypes. "
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    ABSTRACT: Mining of the genome for lipid genes has since the early 1970s helped to shape our understanding of how triglycerides are packaged (in chylomicrons), repackaged (in very low density lipoproteins; VLDL), and hydrolyzed, and also how remnant and low-density lipoproteins (LDL) are cleared from the circulation. Gene discoveries have also provided insights into high-density lipoprotein (HDL) biogenesis and remodeling. Interestingly, at least half of these key molecular genetic studies were initiated with the benefit of prior knowledge of relevant proteins. In addition, multiple important findings originated from studies in mouse, and from other types of non-genetic approaches. Although it appears by now that the main lipid pathways have been uncovered, and that only modulators or adaptor proteins such as those encoded by LDLRAP1, APOA5, ANGPLT3/4, and PCSK9 are currently being discovered, genome wide association studies (GWAS) in particular have implicated many new loci based on statistical analyses; these may prove to have equally large impacts on lipoprotein traits as gene products that are already known. On the other hand, since 2004 - and particularly since 2010 when massively parallel sequencing has become de rigeur - no major new insights into genes governing lipid metabolism have been reported. This is probably because the etiologies of true Mendelian lipid disorders with overt clinical complications have been largely resolved. In the meantime, it has become clear that proving the importance of new candidate genes is challenging. This could be due to very low frequencies of large impact variants in the population. It must further be emphasized that functional genetic studies, while necessary, are often difficult to accomplish, making it hazardous to upgrade a variant that is simply associated to being definitively causative. Also, it is clear that applying a monogenic approach to dissect complex lipid traits that are mostly of polygenic origin is the wrong way to proceed. The hope is that large-scale data acquisition combined with sophisticated computerized analyses will help to prioritize and select the most promising candidate genes for future research. We suggest that at this point in time, investment in sequence technology driven candidate gene discovery could be recalibrated by refocusing efforts on direct functional analysis of the genes that have already been discovered. This article is part of a Special Issue entitled: From Genome to Function.
    Full-text · Article · May 2014 · Biochimica et Biophysica Acta
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    • "Lipodystrophy, familial partial, type 2 PLIN1 Perilipin 1 613877; 170290 [57] Lipodystrophy, familial partial, type 4 PPARG Peroxisome proliferator activated receptor gamma 601487; 604367 [64] Lipodystrophy, familial partial type 3 PTRF RNA polymerase 1 and transcript release factor 603198; 613327 [63] Lipodystrophy, congenital generalized, type 4 ZMPSTE24 Zinc metalloproteinase STE24 606480; 608612 [5] Mandibuloacral dysplasia with lipodystrophy 2) Inherited insulin resistance and obesity syndromes: elevated triglycerides and depressed HDL cholesterol INSR Insulin receptor 246200; 262190; 147670 [87] [137] Group of related disorders, including Leprechaunism (Donahue syndrome), Rabson–Mendenhall syndrome and Type A insulin resistance LEP Leptin 164160 [123] 3) Maturity-onset diabetes of the young (MODY) syndromes HNF1A Hepatic nuclear factor 1-alpha 142410; 600496 [49] [7] MODY type 3; some individuals have metabolic syndrome with elevated triglyceride levels HNF4A Hepatic nuclear factor 4-alpha 600281; 600496 [181] MODY type 4; some individuals have low triglyceride levels 4) Monogenic disorders of bile acid metabolism and cholesterol biosynthesis SLC10A2 Ileal sodium bile salt transporter 601295; 613291 [138] Primary bile acid malabsorption, with congenital diarrhea, steatorrhea, and reduced plasma cholesterol DHCR7 Sterol delta-7 reductase 270400; 602858 [136] Children with Smith–Lemli–Opitz syndrome have reduced levels of total cholesterol 5) Monogenic multisystem disorders with incidental dyslipidemia FBN1 Fibrillin 1 134797 [61] Unusual single family with Marfan syndrome, progeroid features and hypertriglyceridemia G6PC Glucose-6-phosphatase 613742; 232200 [106] Type 1a glycogen storage disease (von Geirke); hypertriglyceridemia can be severe GK Glycerol kinase 300474; 307030 [198] Glycerol kinase deficiency causes factitious hypertriglyceridemia JAG1 Jagged 1 118450; 601920 [100] Children with Alagille syndrome show increased levels of total and LDL cholesterol and triglycerides SMPD1 Sphingomyelin phosphodiesterase 1 607608; [102] Atypical single family with Niemann Pick disease type B and very low HDL cholesterol TNFRSF6 Tumor necrosis factor receptor superfamily member 6 601859; 134637 [9] Atypical single family with autoimmune lymphoproliferative syndrome, splenomegaly, cytopenia and hypertriglyceridemia Table 3 Mouse studies 1) into the molecular genetics of human dyslipidemia; 2) into genomic regions/genes that control plasma lipid levels in mice, and studies that 3) happened to reveal dyslipidemic phenotypes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mining of the genome for lipid genes has since the early 1970s helped to shape our understanding of how triglycerides are packaged (in chylomicrons), repackaged (in very low density lipoproteins; VLDL), and hydrolyzed, and also how remnant and low-density lipoproteins (LDL) are cleared from the circulation. Gene discoveries have also provided insights into high-density lipoprotein (HDL) biogenesis and remodeling. Interestingly, at least half of these key molecular genetic studies were initiated with the benefit of prior knowledge of relevant proteins. In addition, multiple important findings originated from studies in mouse, and from other types of non-genetic approaches. Although it appears by now that the main lipid pathways have been uncovered, and that only modulators or adaptor proteins such as those encoded by LDLRAP1, APOA5, ANGPLT3/4, and PCSK9 are currently being discovered, genome wide association studies (GWAS) in particular have implicated many new loci based on statistical analyses; these may prove to have equally large impacts on lipoprotein traits as gene products that are already known. On the other hand, since 2004 - and particularly since 2010 when massively parallel sequencing has become de rigeur - no major new insights into genes governing lipid metabolism have been reported. This is probably because the etiologies of true Mendelian lipid disorders with overt clinical complications have been largely resolved. In the meantime, it has become clear that proving the importance of new candidate genes is challenging. This could be due to very low frequencies of large impact variants in the population. It must further be emphasized that functional genetic studies, while necessary, are often difficult to accomplish, making it hazardous to upgrade a variant that is simply associated to being definitively causative. Also, it is clear that applying a monogenic approach to dissect complex lipid traits that are mostly of polygenic origin is the wrong way to proceed. The hope is that large-scale data acquisition combined with sophisticated computerized analyses will help to prioritize and select the most promising candidate genes for future research. We suggest that at this point in time, investment in sequence technology driven candidate gene discovery could be recalibrated by refocusing efforts on direct functional analysis of the genes that have already been discovered. This article is part of a Special Issue entitled: From Genome to Function.
    Full-text · Article · Jan 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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