A newly identified splice site mutation in ZMPSTE24 causes restrictive dermopathy in the Middle East.

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.

Effects of partial liquid ventilation with perfluorodecalin in the juvenile rabbit lung after saline injury.

OBJECTIVE: To evaluate the feasibility of using the perfluorochemical, perfluorodecalin, for partial liquid ventilation (PLV) with respect to gas exchange and lung mechanics in normal and saline-injured lungs of juvenile rabbits. DESIGN: Experimental, prospective, randomized, controlled study. SETTING: Physiology laboratory at a university medical school. SUBJECTS: Seventeen juvenile rabbits assigned to three groups. INTERVENTIONS: The conventional mechanical ventilation (CMV)-injury group (n = 5) was treated with CMV after establishing a lung injury; the PLV-injury group (n = 6) was treated with PLV after lung injury; and the PLV-healthy group (n = 6) was supported with PLV without lung injury. Lung injury was created by repeated saline lung lavages. PLV-treated animals received a single dose of intratracheal perfluorodecalin at a volume equal to the measured preinjury gas functional residual capacity (functional residual capacity = 18.6+/-1.5 [SEM] mL/kg). MEASUREMENTS AND MAIN RESULTS: Sequential measurements of total respiratory compliance and arterial blood chemistries were performed in all groups. Oxygenation index (OI) and ventilation efficiency index were calculated. After lung injury, there was a significant (p < .05) decrease in PaO2, total respiratory compliance, and ventilation efficiency index and an increase in OI and PaCO2. In the PLV-injury group, PLV significantly (p < .05) improved PaO2 (+60%) and OI (-33%) over time. Compliance was significantly (p < .05) higher (90%) than in the CMV-injury group over time. CONCLUSIONS: These results demonstrate that PLV with perfluorodecalin improved oxygenation and increased respiratory compliance in the saline-injured rabbit lung. In addition, similar to the effects of several other perfluorochemical liquids on normal lungs, pulmonary administration of perfluorodecalin was associated with a small impairment in gas exchange and a significant decrease in lung compliance in the juvenile rabbit model.