Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63

E. Waanders, H. Venselaar, R. H M te Morsche, D. B. de Koning, Patrick Sequeira Kamath, Vicente Torres, S. Somlo, J. P H Drenth

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Polycystic liver disease (PCLD) is characterized by intralobular bile duct cysts in the liver. It is caused by mutations in PRKCSH, encoding hepatocystin, and SEC63, encoding Sec63p. The main goals of this study were to screen for novel mutations and to analyze mutations for effects on protein structure and function. We screened 464 subjects including 76 probands by direct sequencing or conformation-sensitive capillary electrophoresis. We analyzed the effects of all known and novel mutations using a combination of splice site recognition, evolutionary conservation, secondary and tertiary structure predictions, P. olyP. hen, and pM. ut and sift. We identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non-sense mutations, and eight missense mutations. Out of 48 PCLD mutations, 13 were predicted to affect splicing. Most mutations were located in highly conserved regions and homology modeling for two domains of Sec63p showed severe effects of the residue substitutions. In conclusion, we identified 26 novel mutations associated with PCLD and we provide in silico analysis in order to delineate the role of these mutations.

Original languageEnglish (US)
Pages (from-to)47-56
Number of pages10
JournalClinical Genetics
Volume78
Issue number1
DOIs
StatePublished - 2010

Fingerprint

Mutation
Genes
INDEL Mutation
Polycystic liver disease
Choledochal Cyst
Capillary Electrophoresis
Missense Mutation
Computer Simulation
Liver
Proteins

Keywords

  • Homology modeling
  • Polycystic liver disease
  • PRKCSH
  • SEC63
  • Structural effects

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Medicine(all)

Cite this

Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. / Waanders, E.; Venselaar, H.; te Morsche, R. H M; de Koning, D. B.; Kamath, Patrick Sequeira; Torres, Vicente; Somlo, S.; Drenth, J. P H.

In: Clinical Genetics, Vol. 78, No. 1, 2010, p. 47-56.

Research output: Contribution to journalArticle

Waanders, E. ; Venselaar, H. ; te Morsche, R. H M ; de Koning, D. B. ; Kamath, Patrick Sequeira ; Torres, Vicente ; Somlo, S. ; Drenth, J. P H. / Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. In: Clinical Genetics. 2010 ; Vol. 78, No. 1. pp. 47-56.
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AU - Kamath, Patrick Sequeira

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