Document Detail

A newly identified splice site mutation in ZMPSTE24 causes restrictive dermopathy in the Middle East.
MedLine Citation:
PMID:  18671782     Owner:  NLM     Status:  MEDLINE    
Restrictive dermopathy (RD) is a severe neonatal inherited skin syndrome of which children die shortly after birth. Clinical features include intrauterine growth retardation, taut translucent and easily eroded skin, multiple joint ankylosis and distinct facial features. RD is usually caused by homozygous or compound heterozygous mutations in ZMPSTE24, predicted to cause loss of function of the encoded zinc metalloproteinase STE24. ZMPSTE24 is essential for the processing of the nuclear intermediate filament protein prelamin A. We report two distantly related children from the United Arab Emirates with RD. Remarkably, they lived up to 2 months, suggesting some residual function of the mutant protein. We sought to confirm the diagnosis by thorough microscopic analysis of patient skin, to identify the causative mutation and to study its functional consequences. A skin biopsy was obtained and processed for light and electron microscopy. Peripheral blood leucocytes were used for DNA and RNA isolation, and detection of prelamin A by immunofluorescence. Analysis of the skin confirmed the earlier reported densely packed collagen bundles and lack of elastin fibres. In both patients a homozygous splice site mutation c.627+1G>C in ZMPSTE24 was identified. Analysis of the ZMPSTE24 mRNA revealed an in-frame exon 5 skipping. Accumulation of prelamin A could be detected at the nuclear envelope of patient blood lymphocytes. We thus report the first splice site mutation in ZMPSTE24, which is likely to be a founder mutation in the United Arab Emirates. The accumulation of prelamin A at the nuclear periphery is consistent with defective ZMPSTE24 function. Interestingly, a regular blood sample can be used to investigate prelamin A accumulation.
C S Sander; N Salman; M van Geel; J L V Broers; A Al-Rahmani; F Chedid; I Hausser; V Oji; K Al Nuaimi; T G Berger; V L R M Verstraeten
Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-07-30
Journal Detail:
Title:  The British journal of dermatology     Volume:  159     ISSN:  1365-2133     ISO Abbreviation:  Br. J. Dermatol.     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-10-06     Completed Date:  2008-12-31     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0004041     Medline TA:  Br J Dermatol     Country:  England    
Other Details:
Languages:  eng     Pagination:  961-7     Citation Subset:  IM    
Department of Dermatology, Tawam Hospital in Affiliation with John Hopkins medicine, PO Box 15258, Al Ain, United Arab Emirates.
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MeSH Terms
Elastic Tissue / abnormalities*
Founder Effect
Infant, Newborn
Membrane Proteins / genetics*,  metabolism
Metalloendopeptidases / genetics*,  metabolism
Mutation / genetics*
Nuclear Proteins / genetics*,  metabolism
Protein Precursors / genetics*,  metabolism
RNA Splice Sites / genetics
Skin Abnormalities / genetics*,  pathology
Skin Diseases, Genetic / genetics*,  pathology
United Arab Emirates
Reg. No./Substance:
0/Membrane Proteins; 0/Nuclear Proteins; 0/Protein Precursors; 0/RNA Splice Sites; 0/prelamin A; EC 3.4.24.-/Metalloendopeptidases; EC protein, human

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