title: Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations.
abstract: Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is a hereditary and severe form of polycystic disease affecting the kidneys and biliary tract with an estimated incidence of 1 in 20,000 live births. The clinical spectrum is widely variable: up to 50% of affected neonates die shortly after birth, whereas others survive to adulthood. Mutations at a single locus, polycystic kidney and hepatic disease 1 (PKHD1), are responsible for all typical forms of ARPKD. Mutation detection was performed in PKHD1 by DHPLC in 85 affected, unrelated individuals. Seventy-four amplicons were amplified and analyzed from the PKHD1 genomic locus. Sequence variants were considered pathogenic when they were not observed in 160 control individuals (320 chromosomes). For purposes of genotype-phenotype comparisons, families were stratified by clinical presentation into two groups: the severe perinatal group, in which at least one affected child presented with perinatal disease and neonatal demise, and the less severe, nonperinatal group, in which none of the affected children died in the neonatal period. Forty-one mutations were found in 55 affected disease chromosomes; 32 of these mutations have not been reported previously. Mutations were distributed throughout the portions of gene encoding the predicted extracellular portion of the protein product. The most commonly encountered mutation, T36M, was found in 8 of 55 disease chromosomes. Amino acid substitutions were found to be more commonly associated with a nonlethal presentation, whereas chain terminating mutations were more commonly associated with neonatal demise (chi(2) = 11.54, P = 0.003). All patients who survive the neonatal period have at least one amino acid substitution mutation, suggesting that such substitutions produce milder disease through production of partially functional protein products. The nature of the germline mutations in ARPKD plays a significant role in determining clinical outcome.
authors.affiliation: Departments of Internal Medicine and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Furu
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Onuchic
authors.forename: Ali
authors.initials: A
authors.lastname: Gharavi
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Hou
authors.forename: Ernie L
authors.initials: EL
authors.lastname: Esquivel
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nagasawa
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Ellis
authors.initials: E
authors.lastname: Avner
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Germino
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Guay-Woodford
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
mesh_terms: D000596:Amino Acids; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005091:Exons; D005808:Genes, Recessive; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics*; D011110:Polymorphism, Genetic; D011379:Prognosis; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000596:Amino Acids; D017931:DNA Primers; C451750:PKHD1 protein, human; D011956:Receptors, Cell Surface