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A nonsense mutation of PEPD in four Amish children with prolidase deficiency

Heng Wang1, Biji T Kurien, David Lundgren

  • 1Das Deutsch Center (DDC) Clinic for Special Needs Children, Middlefield, Ohio 44062, USA. wang@ddclinic.org

American Journal of Medical Genetics. Part A
|February 14, 2006
PubMed

Insights

This study identifies a novel mutation in the PEPD gene causing severe prolidase deficiency in Amish children. The findings highlight a unique presentation of the disorder in the United States.

Area of Science:

  • Biochemistry
  • Genetics
  • Pediatrics

Background:

  • Prolidase deficiency is a rare genetic disorder affecting cytosolic enzyme activity.
  • The peptidase D (PEPD) gene encodes prolidase, crucial for peptide hydrolysis.
  • Previous reports predominantly feature skin ulcers as the primary symptom.

Purpose of the Study:

  • To report the first cases of prolidase deficiency in the Amish population in the United States.
  • To characterize the clinical and genetic features of severe prolidase deficiency in affected children.
  • To investigate the molecular basis of the observed severe phenotype.

Main Methods:

  • Clinical evaluation of four Amish children with suspected prolidase deficiency.
  • Biochemical assays to measure prolidase activity.
  • Genomic DNA sequencing of the PEPD gene to identify mutations.

Main Results:

  • Four Amish children presented with a severe phenotype including infections, hepatosplenomegaly, and thrombocytopenia, differing from typical presentations.
  • All patients exhibited characteristic facial features, skin ulcers, multisystem involvement, and massive imidodipeptiduria.
  • A homozygous single nucleotide mutation (c.793 T > C) in exon 11 of the PEPD gene, leading to a premature stop-codon (p.R265X), was identified in all patients.

Conclusions:

  • This study reports the first cases of prolidase deficiency in the Amish population and the United States.
  • The identified PEPD gene mutation (p.R265X) is associated with a severe, multisystemic phenotype.
  • The specific type of PEPD mutation may influence the severity of prolidase deficiency.

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