Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype

Shackleton, Sue; Smallwood, Dawn T.; Clayton, Peter T.; Wilson, Louise C.; Agarwal, Anil K.; Garg, Abhimanyu; Trembath, Richard C.

doi:10.1136/jmg.2004.029751

Cited by 108 publications

(99 citation statements)

References 25 publications

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“…In contrast, there is almost no information regarding the structure of ZMPSTE24, the domains of the enzyme involved in catalysis, or how HIV-PIs might interfere with enzyme activity. ZMPSTE24 contains a zinc-binding HEXXH motif (residues 335-339) that is required for catalysis (18,19), and missense mutations at residues 265 and 340 dramatically reduce enzymatic activity (10,21). However, whether HIV-PIs bind in the vicinity of those residues is unknown.…”

Section: Discussionmentioning

confidence: 99%

HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells

Coffinier

Hudon

Farber

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

123

135

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Section: Discussionmentioning

confidence: 99%

HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells

Coffinier

Hudon

Farber

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

123

135

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“…The first patient, carrying compound nonsense and missense mutations, had been diagnosed as a severe progeroid phenotype and died at the age of 2 years. 14 The second patient carried a homozygous ZMPSTE24 frameshift deletion associated with an LMNA heterozygous nonsense mutation that 'rescued' the patient's phenotype, most probably by reducing to half the amounts of accumulated prelamin A, as in the double-knockout Zmpste24 À/À Lmna +/À mice. 15,31 This patient showed features compatible with a severe form of MADB, but was described as being affected with HGPS.…”

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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“…Compound heterozygous and homozygous missense mutations in ZMPSTE24 have been reported to result in a case of mandibuloacral disease (MAD) and a progeroid-like phenotype in another individual [70,71]. 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].…”

Section: The Secondary Laminopathiesmentioning

confidence: 99%

Mouse models of the laminopathies

Stewart

Kozlov

Fong

et al. 2007

Experimental Cell Research

107

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The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A-type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the Atype lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.

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Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype

Cited by 108 publications

References 25 publications

HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells

HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells

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

Mouse models of the laminopathies

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