Faculty Collaboration Database

Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations. J Am Soc Nephrol 2003 Aug;14(8):2004-14

Date

07/23/2003

Pubmed ID

12874454

DOI

10.1097/01.asn.0000078805.87038.05

Scopus ID

2-s2.0-0042844709 (requires institutional sign-in at Scopus site)   106 Citations

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.

Author List

Furu L, Onuchic LF, Gharavi A, Hou X, Esquivel EL, Nagasawa Y, Bergmann C, Senderek J, Avner E, Zerres K, Germino GG, Guay-Woodford LM, Somlo S

Author

Ellis D. Avner MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acids
Child
Child, Preschool
DNA Mutational Analysis
DNA Primers
Exons
Genes, Recessive
Genotype
Heterozygote
Humans
Infant
Infant, Newborn
Models, Genetic
Mutation
Phenotype
Polycystic Kidney Diseases
Polymorphism, Genetic
Prognosis
Protein Structure, Tertiary
Receptors, Cell Surface
Time Factors
Treatment Outcome