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

Abstract

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,

Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells

“…Subcutaneous lipoatrophy gave her a muscular pseudo-hypertrophic appearance. Molecular genetic diagnosis allowed the identification of a new homozygous mutation in the ZMPSTE24/FACE1 gene’s exon 10: c.1274T > C, p.(Leu425Pro), confirming the B-type Mandibuloacral dysplasia phenotype in the patient [ 19 ].…”

“…Patients affected with mandibuloacral dysplasia type B (MAD-B), carry biallelic mutations in the FACE1/ZMPSTE24 gene. As a consequence, the last cleavage step of Prelamin A maturation is only partially performed, leading to the accumulation of wild type, permanently farnesylated and toxic Prelamin A isoforms [ 17 , 18 , 19 ].…”

Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies

“…In individuals affected by MADB, no sequence alteration in LMNA has been detected, suggesting a different genetic cause than in MADA [Simha et al, 2003]. Indeed, biallelic mutations in the ZMPSTE24 gene have been identified in patients with MADB Miyoshi et al, 2008;Cunningham et al, 2010;Ahmad et al, 2011;Yaou et al, 2011]. ZMPSTE24 encodes a zinc metalloproteinase which is required for posttranslational processing of the precursor molecule of lamin A, called prelamin A [Barrowman and Michaelis, 2009]: first, ZMPSTE24 cleaves off the last 3 amino acids of the farnesylated prelamin A.…”

Lipodystrophic laminopathies: Diagnostic clues

“… MADA[ 73 – 78 ] LMNA 2–4 >15 PARTIAL Metabolic syndrome Delayed closure of fontanels, wormian bones. (2 cases >40) MADB[ 79 – 83 ] ZMPSTE24 perinatal >20 GENERALIZED Metabolic syndrome Delayed closure of fontanels, wormian bones, SC nodules NGPS[ 71 , 72 ] BANF1 >30 GENERALIZED Pulmonary hypertension, respiratory restrictive pattern Profound skeletal abnormalities “THE CHRONIC PROGERIA” APS: Atypical progeria syndrome; HGPS: Hutchinson-Gilford Progeria Syndrome; MADA: Type A Madibuloacral dysplasia; MADB: Type B Madibuloacral dysplasia; NGPS: Nestor-Guillermo Progeria Syndrome. …”

“…MADB (MIM: #608612) is a secondary laminopathy, resulting from homozygous variants in zinc metalloprotease ZMPSTE24 (1p34.2) [ 79 ]. Phenotype appears at birth, with postnatal growth retardation and difficult to feed [ 80 ].…”