Novel mutations in the duplicated region of PKD1 gene.

Autosomal dominant polycystic kidney disease (ADPKD) exhibits a genetically heterogeneous transmission involving at least three different genes. PKD1 gene linked mutations are responsible for the disease in about 85% of ADPKD cases. The search for mutations is a very important step in understanding the molecular mechanisms underlying ADPKD. We undertook this study using denaturing gradient gel electrophoresis (DGGE), after a stage of long range PCR, to scan for mutations in the duplicated region of the PKD1 gene in French ADPKD families. This allowed us to identify eight novel mutations and several polymorphisms: among the mutations, three are nonsense mutations, two are deletions in the coding sequence leading to frameshift mutations, one is a splice mutation and two are highly probable missense mutations. In this paper, we also provide a review of the mutations reported so far which are widespread throughout the gene. Although no clear hot spot for mutation is apparent, we will focus on some clustering observed.

DGGE screening of PKD1 gene reveals novel mutations in a large cohort of 146 unrelated patients.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most commonly inherited renal diseases. ADPKD is a genetically heterogeneous disorder involving at least three different genes. PKD1, the major locus mapped to chromosome 16p13.3 accounts for approximately 85% of ADPKD cases. The search for mutations is a very important step in understanding the molecular mechanisms underlying ADPKD. Despite intense screening by many groups, only a small number of mutations have been described so far. We undertook the first study using denaturing gradient gel electrophoresis (DGGE) to scan for mutations in the non-duplicated region of the PKD1 gene in a large cohort of 146 French unrelated ADPKD patients. We successfully identified novel mutations: 3 are frameshift mutations, 2 nonsense mutations, 2 missense mutations, 1 is an insertion in the frame of 9 nucleotides, 3 intronic variations and several polymorphisms. One of these mutations is the fourth de novo mutation described in this gene. We also describe a family with possible clinical anticipation. DGGE is an effective method for detecting nucleotide changes in the PKD1 gene.

HLA class II typing and idiopathic IgA nephropathy (IgAN): DQB1*0301, a possible marker of unfavorable outcome.

Previous studies have reported associations between HLA antigens and Idiopathic IgA Nephropathy (IgAN). Nevertheless most of the studies were performed by serology. Thus we decided to perform the HLA class II typing of 58 patients by molecular biology techniques. We report a small increase of DRB1*04. But the main result of our study is the identification of a strong association between HLA DQB1*0301 and IgAN patients with an unfavorable outcome.

[Autosomal dominant polycystic kidney and genetic markers of chromosome 16]. / Polykystose rénale autosomique dominante et marqueurs génétiques du chromosome 16.

The mutation for autosomal dominant polycystic kidney disease (APKD) has been mapped by linkage analysis on the distal part of the short arm of chromosome 16. We present in this study the results of linkage analysis using the two most tightly linked DNA markers (3'HVR and 24-1) in 183 members of 14 families of a same ethnic origin. We have constructed haplotypes using these two polymorphic probes, and compared the frequency of these on the normal and the affected chromosome. No evidence of linkage heterogeneity was found in our population.