The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein

Christopher J. Ward; Marie C. Hogan; Sandro Rossetti; Denise Walker; Tam Sneddon; Xiaofang Wang; Vicky Kubly; Julie M. Cunningham; Robert Bacallao; Masahiko Ishibashi; Dawn S. Milliner; Vicente E. Torres; Peter C. Harris

doi:10.1038/ng833

The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein

Christopher J. Ward, Marie C. Hogan, Sandro Rossetti, Denise Walker, Tam Sneddon, Xiaofang Wang, Vicky Kubly, Julie M. Cunningham, Robert Bacallao, Masahiko Ishibashi, Dawn S. Milliner, Vicente E. Torres, Peter C. Harris

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Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of collecting ducts and by biliary dysgenesis and is an important cause of renal- and liver-related morbidity and mortality. Genetic analysis of a rat with recessive polycystic kidney disease revealed an orthologous relationship between the rat locus and the ARPKD region in humans; a candidate gene was identified. A mutation was characterized in the rat and screening the 66 coding exons of the human ortholog (PKHD1) in 14 probands with ARPKD revealed 6 truncating and 12 missense mutations; 8 of the affected individuals were compound heterozygotes. The PKHD1 transcript, approximately 16 kb long, is expressed in adult and fetal kidney, liver and pancreas and is predicted to encode a large novel protein, fibrocystin, with multiple copies of a domain shared with plexins and transcription factors. Fibrocystin may be a receptor protein that acts in collecting-duct and biliary differentiation.

Original language	English (US)
Pages (from-to)	259-269
Number of pages	11
Journal	Nature Genetics
Volume	30
Issue number	3
DOIs	https://doi.org/10.1038/ng833
State	Published - Mar 2002

ASJC Scopus subject areas

Genetics

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title = "The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein",

abstract = "Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of collecting ducts and by biliary dysgenesis and is an important cause of renal- and liver-related morbidity and mortality. Genetic analysis of a rat with recessive polycystic kidney disease revealed an orthologous relationship between the rat locus and the ARPKD region in humans; a candidate gene was identified. A mutation was characterized in the rat and screening the 66 coding exons of the human ortholog (PKHD1) in 14 probands with ARPKD revealed 6 truncating and 12 missense mutations; 8 of the affected individuals were compound heterozygotes. The PKHD1 transcript, approximately 16 kb long, is expressed in adult and fetal kidney, liver and pancreas and is predicted to encode a large novel protein, fibrocystin, with multiple copies of a domain shared with plexins and transcription factors. Fibrocystin may be a receptor protein that acts in collecting-duct and biliary differentiation.",

author = "Ward, {Christopher J.} and Hogan, {Marie C.} and Sandro Rossetti and Denise Walker and Tam Sneddon and Xiaofang Wang and Vicky Kubly and Cunningham, {Julie M.} and Robert Bacallao and Masahiko Ishibashi and Milliner, {Dawn S.} and Torres, {Vicente E.} and Harris, {Peter C.}",

note = "Funding Information: We thank the patients and their families for taking part in the study, M. El Youssef, J. Gloor, E.N. Haugen, P.S. Kamath and B.Z. Morgenstern for referring patients, and P. Fraught, M. de Andrade and E.J. Atkinson for assistance. Charles River Japan are thanked for the gift of the breeding pairs of PCK rats. The work was supported by grants from the National Institutes of Health, the PKD Foundation (to S.R. and M.H.), the Mayo Graduate School and Foundation, Mayo Cancer Center and the Wellcome Trust.",

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AU - Ward, Christopher J.

AU - Hogan, Marie C.

AU - Rossetti, Sandro

AU - Walker, Denise

AU - Sneddon, Tam

AU - Wang, Xiaofang

AU - Kubly, Vicky

AU - Cunningham, Julie M.

AU - Bacallao, Robert

AU - Ishibashi, Masahiko

AU - Milliner, Dawn S.

AU - Torres, Vicente E.

AU - Harris, Peter C.

N1 - Funding Information: We thank the patients and their families for taking part in the study, M. El Youssef, J. Gloor, E.N. Haugen, P.S. Kamath and B.Z. Morgenstern for referring patients, and P. Fraught, M. de Andrade and E.J. Atkinson for assistance. Charles River Japan are thanked for the gift of the breeding pairs of PCK rats. The work was supported by grants from the National Institutes of Health, the PKD Foundation (to S.R. and M.H.), the Mayo Graduate School and Foundation, Mayo Cancer Center and the Wellcome Trust.

PY - 2002/3

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N2 - Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of collecting ducts and by biliary dysgenesis and is an important cause of renal- and liver-related morbidity and mortality. Genetic analysis of a rat with recessive polycystic kidney disease revealed an orthologous relationship between the rat locus and the ARPKD region in humans; a candidate gene was identified. A mutation was characterized in the rat and screening the 66 coding exons of the human ortholog (PKHD1) in 14 probands with ARPKD revealed 6 truncating and 12 missense mutations; 8 of the affected individuals were compound heterozygotes. The PKHD1 transcript, approximately 16 kb long, is expressed in adult and fetal kidney, liver and pancreas and is predicted to encode a large novel protein, fibrocystin, with multiple copies of a domain shared with plexins and transcription factors. Fibrocystin may be a receptor protein that acts in collecting-duct and biliary differentiation.

AB - Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of collecting ducts and by biliary dysgenesis and is an important cause of renal- and liver-related morbidity and mortality. Genetic analysis of a rat with recessive polycystic kidney disease revealed an orthologous relationship between the rat locus and the ARPKD region in humans; a candidate gene was identified. A mutation was characterized in the rat and screening the 66 coding exons of the human ortholog (PKHD1) in 14 probands with ARPKD revealed 6 truncating and 12 missense mutations; 8 of the affected individuals were compound heterozygotes. The PKHD1 transcript, approximately 16 kb long, is expressed in adult and fetal kidney, liver and pancreas and is predicted to encode a large novel protein, fibrocystin, with multiple copies of a domain shared with plexins and transcription factors. Fibrocystin may be a receptor protein that acts in collecting-duct and biliary differentiation.

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The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein

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