Focal Segmental Glomerulosclerosis in Patients with Mandibuloacral Dysplasia Owing to ZMPSTE24 Deficiency

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Abstract
Background: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder characterized by skeletal abnormalities such as hypoplasia of the mandible and clavicles and acro-osteolysis. Other features include cutaneous atrophy and lipodystrophy. Two genetic loci are known for MAD: lamin A/C ( LMNA), encoding structural nuclear lamina proteins, and zinc metalloproteinase ( ZMPSTE24), a membrane-bound endoprotease involved in post-translational proteolytic cleavage of carboxy terminal residues of prelamin A to form mature lamin A. Methods: Mutational analysis of ZMPSTE24 in an additional patient with MAD and determination of functional activity of mutant ZMPSTE24 in a yeast growth arrest pheromone diffusion (halo) assay. Results: We previously reported a Belgian woman with MAD who had ZMPSTE24 mutations and died of complications of chronic renal failure at the age of 27.5 years. We now report a 37-year-old Australian man with MAD who also had compound heterozygous mutations in the ZMPSTE24 gene, a null mutation, Phe361fsX379, and a missense mutation, Asn265Ser, which is partially active in the yeast complementation assay. He also developed end-stage renal disease and, despite receiving a cadaveric renal transplantation, died prematurely at the age of 37 years. Renal biopsies of both patients revealed focal segmental glomerulosclerosis, and the female patient had the collapsing variant. Conclusion: These observations suggest focal segmental glomerulosclerosis as a phenotypic manifestation in patients with ZMPSTE24 deficiency.