A newly identified splice site mutation inZMPSTE24causes restrictive dermopathy in the Middle East

Abstract

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.

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

“…Moreover, all RD-related mutations lead to a complete absence of the ZMPSTE24 protein or to null activity, consequently causing the accumulation of prelamin A and an absence of mature lamin A. 11,16,25 Two patients carrying ZMPSTE24 mutations had progeroid features of variable severity. 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.…”

“…Apart from one, 24 the 23 patients with typical RD features had either homozygous or compound heterozygous null mutations (nonsense, insertions or deletions) 10,11,17,[25][26][27][28][29][30] or very large in-frame deletions sometimes resulting from splice site mutations 10,11,16 in the ZMPSTE24 gene. Moreover, all RD-related mutations lead to a complete absence of the ZMPSTE24 protein or to null activity, consequently causing the accumulation of prelamin A and an absence of mature lamin A.…”

“…10,11,[14][15][16] Whereas the ZMPSTE24 mutations found in MADB encoded a protein with considerably reduced residual activity, the mutations found in RD led to null ZMPSTE24 activity, strongly suggesting a positive correlation between residual enzyme activity, accumulated prelamin A levels and the severity of the phenotype. 17 In Zmpste24-knockout mice, severe growth retardation, skeletal abnormalities, including small mandible, lipodystrophy, cardiomyopathy and muscular dystrophy, were reported, as well as premature death, with these features being associated with a complete absence of mature lamin A and an exclusive production of prelamin A.…”

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update

“…On the opposite, in typical MAD-B, lipodystrophy is generalized, an earlier age of onset is observed (often during the first year of life) and the median age of death is 30 years. Other mutations were found in additional cases of RD [15][16][17][18][19][20][21] and progeroid syndromes phenotypically overlapping with MAD and HGPS that can be nosologically classified as MAD-B, given the common molecular basis, involving ZMPSTE24 deficiency. 13,[22][23][24][25][26][27][28] RD, MAD-B and HGPS share a common pathophysiological mechanism based on the abnormal accumulation of a wild type or modified lamin A precursors.…”

Accelerated ageing: from mechanism to therapy through animal models

“…1). In addition, mutations in ZMPSTE24 have also been found in several human progeroid syndromes, such as mandibuloacral dysplasia (MAD) and restrictive dermopathy (RD) (Agarwal et al 2003;Navarro et al 2005;Shackleton et al 2005;Sander et al 2008), providing additional support to the relevance of Zmpste24 -/-mice as a model for studying accelerated ageing. Interestingly, accumulation of prenylated progerin has also been associated with normal ageing, a finding that expands considerably the interest of Zmpste24-deficient mice and other related animal models of progeria (Scaffidi and Misteli 2006 Transcriptional and biochemical alterations in Zmpste24 2/2 progeroid mice…”