Genomic structure of the gene for the human P1 protein (MCM3) and its exclusion as a candidate for autosomal recessive polycystic kidney disease

Hofmann, Yvonne; Becker, Jutta; Wright, Felicia; Avner, Ellis D.; Mrug, Michal; Guay‐Woodford, Lisa M.; Somlo, Stefan; Zerres, Klaus; Germino, Gregory G.; Onuchic, Luiz Fernando

doi:10.1038/sj.ejhg.5200426

Cited by 8 publications

(5 citation statements)

References 9 publications

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“…1A). The genes KIAA0057 (Onuchic et al 1999), FLJ10466 (Onuchic et al, in press), MCM3 (Hofmann et al 2000), Interleukin-17 (Rouvier et al 1993), and ML-1 (Kawaguchi et al 2001) have been described elsewhere. Each of these genes either has been excluded as a candidate for PKHD1 or, on the basis of its known function, has been deemed to be an unlikely candidate.…”

Section: Transcription Map Of the Minimal Intervalmentioning

confidence: 99%

PKHD1, the Polycystic Kidney and Hepatic Disease 1 Gene, Encodes a Novel Large Protein Containing Multiple Immunoglobulin-Like Plexin-Transcription–Factor Domains and Parallel Beta-Helix 1 Repeats

Onuchic

Furu

Nagasawa

et al. 2002

The American Journal of Human Genetics

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Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of polycystic kidney disease that presents primarily in infancy and childhood and that is characterized by enlarged kidneys and congenital hepatic fibrosis. We have identified PKHD1, the gene mutated in ARPKD. PKHD1 extends over > or =469 kb, is primarily expressed in human fetal and adult kidney, and includes a minimum of 86 exons that are variably assembled into a number of alternatively spliced transcripts. The longest continuous open reading frame encodes a 4,074-amino-acid protein, polyductin, that is predicted to have a single transmembrane (TM)-spanning domain near its carboxyl terminus, immunoglobulin-like plexin-transcription-factor domains, and parallel beta-helix 1 repeats in its amino terminus. Several transcripts encode truncated products that lack the TM and that may be secreted if translated. The PKHD1-gene products are members of a novel class of proteins that share structural features with hepatocyte growth-factor receptor and plexins and that belong to a superfamily of proteins involved in regulation of cell proliferation and of cellular adhesion and repulsion.

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Section: Transcription Map Of the Minimal Intervalmentioning

confidence: 99%

PKHD1, the Polycystic Kidney and Hepatic Disease 1 Gene, Encodes a Novel Large Protein Containing Multiple Immunoglobulin-Like Plexin-Transcription–Factor Domains and Parallel Beta-Helix 1 Repeats

Onuchic

Furu

Nagasawa

et al. 2002

The American Journal of Human Genetics

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447

452

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“…Two independent groups recently unraveled the PKHD1 gene (9,10). Ward et al identified the human gene by homology to the mutation in the PCK rat model for polycystic kidney disease (11,12), and our group succeeded by positional cloning (13)(14)(15)(16). On genomic DNA, the gene spreads over an expanse of at least 470 kb.…”

mentioning

confidence: 99%

Spectrum of Mutations in the Gene for Autosomal Recessive Polycystic Kidney Disease (ARPKD/PKHD1)

Bergmann¹,

Senderek

Sedlacek

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Autosomal recessive polycystic kidney disease (ARPKD/PKHD1) is an important cause of renal-related and liver-related morbidity and mortality in childhood. Recently mutations in the PKHD1 gene on chromosome 6p21.1-p12 have been identified as the molecular cause of ARPKD. The longest continuous open reading frame (ORF) is encoded by a 67-exon transcript and predicted to yield a 4074 -amino acid protein ("polyductin") of thus far unknown function. By now, a total of 29 different PKHD1 mutations have been described. This study reports mutation screening in 90 ARPKD patients and identifies mutations in 110 alleles making up a detection rate of 61%. Thirty-four of the detected mutations have not been reported previously. Two underlying mutations in 40 patients and one mutation in 30 cases are disclosed, and no mutation was detected on the remaining chromosomes. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. About 45% of the changes were predicted to truncate the protein. All missense mutations were nonconservative, with the affected amino acid residues found to be conserved in the murine polyductin orthologue. One recurrent missense mutation (T36M) likely represents a mutational hotspot and occurs in a variety of populations. Two founder mutations (R496X and V3471G) make up about 60% of PKHD1 mutations in the Finnish population. Preliminary genotype-phenotype correlations could be established for the type of mutation rather than for the site of the individual mutation. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise. PKHD1 mutation analysis is a powerful tool to establish the molecular cause of ARPKD in a given family. Direct identification of mutations allows an unequivocal diagnosis and accurate genetic counseling even in families displaying diagnostic challenges. cbergmann@ukaachen.de

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“…2). KIAA0057 and MCM3 have been excluded as PKHD1 candidates [Onuchic et al, 1999; Hofmann et al, 2000], and IL‐17 and ML‐1 have expression patterns and functions unlikely to be involved with ARPKD pathogenesis. The hCT1642763 gene [Venter et al, 2001] is currently under evaluation, along with several other partial transcripts.…”

Section: Resultsmentioning

confidence: 99%

“…The MCM3‐A/B marker, a single nucleotide polymorphism, has been described previously [Hofmann et al, 2000].…”

Section: Methodsmentioning

confidence: 99%

Refinement of the autosomal recessive polycystic kidney disease (PKHD1) interval and exclusion of an EF hand‐containing gene as aPKHD1candidate gene

et al. 2002

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Autosomal recessive polycystic kidney disease (ARPKD) is an often devastating form of polycystic kidney disease that presents primarily in infancy. The locus, PKHD1 (polycystic kidney and hepatic disease 1), on chromosome 6p21.1-p12, has been linked to all classical forms of this disorder. In previous studies, we cloned the PKHD1 interval in a set of overlapping YACs, converted this YAC-based framework into a BAC/PAC contig, and delimited the critical interval to a region flanked by the markers D6S1714 and D6S1024. We now have refined the genetic interval using new polymorphic markers developed from our BAC/PAC resources. In addition, we have evaluated a recently identified, EF hand-containing gene that maps to the interval of interest, established its transcript sequence, defined its genomic organization, and excluded this new gene as a PKHD1 candidate. Therefore, this study has narrowed the PKHD1 interval and excluded a potentially relevant gene as a PKHD1 candidate gene. This further refinement of the PKHD1 interval will facilitate efforts to identify the PKHD1 gene by positional cloning. These data also provide additional, highly polymorphic markers for haplotype-based diagnostic testing for ARPKD.

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Genomic structure of the gene for the human P1 protein (MCM3) and its exclusion as a candidate for autosomal recessive polycystic kidney disease

Cited by 8 publications

References 9 publications

PKHD1, the Polycystic Kidney and Hepatic Disease 1 Gene, Encodes a Novel Large Protein Containing Multiple Immunoglobulin-Like Plexin-Transcription–Factor Domains and Parallel Beta-Helix 1 Repeats

PKHD1, the Polycystic Kidney and Hepatic Disease 1 Gene, Encodes a Novel Large Protein Containing Multiple Immunoglobulin-Like Plexin-Transcription–Factor Domains and Parallel Beta-Helix 1 Repeats

Spectrum of Mutations in the Gene for Autosomal Recessive Polycystic Kidney Disease (ARPKD/PKHD1)

Refinement of the autosomal recessive polycystic kidney disease (PKHD1) interval and exclusion of an EF hand‐containing gene as aPKHD1candidate gene

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