Gene Map Locus: 16p13.31-p13.12
Gal et al. (1989) studied 10 families in which early manifestation of the disorder was a frequent finding. In all families studied, close linkage was observed between the chromosome 16 alpha-globin marker and the APKD locus.
Germino et al. (1992) demonstrated that the PKD1 gene lies within a 750-kb segment of 16p13.3.
The International Polycystic Kidney Disease Consortium (1995) reported the complete structure of the PKD1 gene and its protein. The PKD1 transcript contains 46 exons. The 14.5-kb PKD1 transcript encodes a 4,304-amino acid protein that has a novel domain architecture. The PKD1 protein, called polycystin, is a glycoprotein with multiple transmembrane domains and a cytoplasmic C-tail. The amino-terminal extracellular half of the protein consists of a mosaic of previously described domains, including leucine-rich repeats flanked by characteristic cysteine-rich structures, and 14 units of a novel 80 amino acid domain. The presence of these domains suggested that the PKD1 protein is an integral membrane protein involved in adhesive protein-protein and protein-carbohydrate interactions in the extracellular compartment. Ward et al. (1996) found widespread PKD1 mRNA expression in adult tissue, with high levels in brain and moderate signal in kidney.
At a point when only 7 mutations in the PKD1 gene had been described,
Peral et al. (1996) reported a systematic
screen covering nearly 80% of the approximately 2.5 kb of translated
transcript that is encoded by a single-copy DNA.
They identified and characterized 6 novel mutations that, together
with the previously described changes, amounted to a detection rate
of 10 to 15% in the population studied.
Study of the PKD1 mutation search in the PKD1 gene is complicated
by the fact that most of the gene lies in a genomic region reiterated
several times elsewhere on chromosome 16.
All (75%) but 3.5 kb at the 3-prime end of the PKD1 transcript (which is
approximately 14 kb in total) is encoded by a region reiterated several
times in a region on 16p termed the homologous gene (HG) area.
The results of the study of Peral et al. (1996)
have important implications for genetic diagnosis of PKD1 because
they indicate that most of the mutations lie within the duplicated
area which is difficult to study.
Neophytou et al. (1996) reported an intragenic
polymorphism.
They considered this intragenic polymorphism to be highly useful in
informative families, given the instability of the PKD1 region.
(601313.0006).
The sequence similarity between the duplicated region precludes specific analysis for mutations and consequently mutations were first identified in the unique 3-prime region of PKD1. Peral et al. (1997) developed a novel approach. This strategy was incorporated in a mutation screen of 100 patients for more than half of the PKD1 exons (exons 22 to 46; 37% of the coding region), including 11 (exons 22 to 32) within the duplicated gene region. Sixty of the patients were also screened for missense mutations in exons 23 to 36. In this way, Peral et al. (1997) identified 11 mutations, 6 within the duplicated region: 3 stop mutations, 3 frameshifting deletions of 1 nucleotide, 2 splicing defects, and 3 possible missense changes. Each mutation was detected in just 1 family, although 1 had been described previously; no mutation hot spot was identified. The nature and distribution of mutations, plus the lack of a clear phenotype/genotype correlation, suggested that the mutations may inactivate the molecule.
SEE ALSO Breuning et al. (1990); Terada and Nakanuma (1988)