Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency.
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.
Agarwal
Anil K
AK
From the Division of Nutrition and Metabolic Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390-9052, USA.
Zhou
Xin J
XJ
Hall
Roger K
RK
Nicholls
Kathy
K
Bankier
Agnes
A
Van Esch
Hilde
H
Fryns
Jean-Pierre
JP
Garg
Abhimanyu
A
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
D008074:Lipoproteins; D008565:Membrane Proteins; D045726:Metalloproteases; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human