A homozygous missense mutation in PEPD encoding peptidase D causes prolidase deficiency associated with hyper-IgE syndrome
ABSTRACT Prolidase deficiency is a complex disease characterized by various skin manifestations accompanied by mental retardation, facial dysmorphism and susceptibility to pyogenic infections.
We assessed a patient presenting a peculiar phenotype combining manifestations of prolidase deficiency with features typical of hyper-IgE syndrome. Mutation analysis was performed using direct PCR amplification and PCR restriction fragment length polymorphism analysis.
We identified a novel homozygous recessive mutation in the PEPD gene, which was found to segregate in the family of the patient with the disease and was not found in a panel of DNA samples representative of all major Druze families living in northern Israel.
Our results suggest that prolidase deficiency associated with hyper-IgE syndrome, a rare disorder, can be caused by mutations in PEPD.
SourceAvailable from: Heidi H KongJournal of the American Academy of Dermatology 06/2010; 62(6):1031-4. DOI:10.1016/j.jaad.2009.12.038 · 5.00 Impact Factor
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ABSTRACT: Point mutations resulting in the substitution of a single amino acid can cause severe functional consequences, but can also be completely harmless. Understanding what determines the phenotypical impact is important both for planning targeted mutation experiments in the laboratory and for analyzing naturally occurring mutations found in patients. Common wisdom suggests using the extent of evolutionary conservation of a residue or a sequence motif as an indicator of its functional importance and thus vulnerability in case of mutation. In this work, we put forward the hypothesis that in addition to conservation, co-evolution of residues in a protein influences the likelihood of a residue to be functionally important and thus associated with disease. While the basic idea of a relation between co-evolution and functional sites has been explored before, we have conducted the first systematic and comprehensive analysis of point mutations causing disease in humans with respect to correlated mutations. We included 14,211 distinct positions with known disease-causing point mutations in 1,153 human proteins in our analysis. Our data show that (1) correlated positions are significantly more likely to be disease-associated than expected by chance, and that (2) this signal cannot be explained by conservation patterns of individual sequence positions. Although correlated residues have primarily been used to predict contact sites, our data are in agreement with previous observations that (3) many such correlations do not relate to physical contacts between amino acid residues. Access to our analysis results are provided at http://webclu.bio.wzw.tum.de/~pagel/supplements/correlated-positions/.PLoS Computational Biology 09/2010; 6(9). DOI:10.1371/journal.pcbi.1000923 · 4.83 Impact Factor
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ABSTRACT: Prolidase deficiency is a rare inherited connective tissue disorder characterised by intractable skin ulceration, lymphoedema, recurrent infections and mild intellectual impairment. We have documented the progress of an affected individual over the past 40 years, illustrated by high quality photographs to demonstrate the natural history of prolidase deficiency.Clinical dysmorphology 07/2011; 20(4):194-9. DOI:10.1097/MCD.0b013e3283486cbd · 0.42 Impact Factor