title: Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency.
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.
  
  
  CONCLUSIONS
  These observations suggest focal segmental glomerulosclerosis as a phenotypic manifestation in patients with ZMPSTE24 deficiency.
authors.affiliation: From the Division of Nutrition and Metabolic Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390-9052, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
authors.forename: Xin J
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Roger K
authors.initials: RK
authors.lastname: Hall
authors.forename: Kathy
authors.initials: K
authors.lastname: Nicholls
authors.forename: Agnes
authors.initials: A
authors.lastname: Bankier
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Garg
mesh_terms: D030981:Acro-Osteolysis / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000595:Amino Acid Sequence; D002968:Clavicle / Q000002:abnormalities; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005121:Extremities / Q000473:pathology*; D017809:Fatal Outcome; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008074:Lipoproteins / Q000172:deficiency / Q000235:genetics*; D008297:Male; D008334:Mandible / Q000002:abnormalities*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D008666:Metalloendopeptidases; D045726:Metalloproteases / Q000172:deficiency / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D016415:Sequence Alignment
chemical_list: D008074:Lipoproteins; D008565:Membrane Proteins; D045726:Metalloproteases; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human