ARE MUTATIONS OF PLCE1 SUFFICIENT TO CAUSE DIFFUSE MESANGIAL SCLEROSIS?

¹R. Gilbert, ²C. Turner, ³J. Gibson, ¹P. Bass, ¹S. Haq, ²E. Cross, ²D. Bunyan, ³A. Collins, ³W. Tapper, ¹J. Needall, ¹B. Dell, ³N. Morton, ³K. Temple, ²D. Robinson. ¹Southampton University Hospitals NHS Trust, Southampton, UK, ²Wessex Regional Genetics Laboratory, Salisbury, UK, ³University of Southampton, Southampton, UK

Aim: We present the first report of an individual homozygous for an apparently pathogenic mutation of PLCE1 who has no clinical renal disease.

Method: Three children from a consanguineous kindred of Pakistani origin with diffuse mesangial sclerosis (DMS) presented with congenital or infantile nephrotic syndrome. Genome-wide single nucleotide polymorphism (SNP) mapping was carried out in the three affected and four of the unaffected individuals. Direct sequencing of the PLCE1 gene was undertaken. In one individual results were confirmed with two additional primer sets. Multiplex ligation-dependent probe amplification (MLPA) analysis was also performed and methylation analysis of an imprinted site on chromosome 10. Microsatellite analysis was carried out by PCR amplification of DNA using primers for polymorphic (CA)n repeat sequences in the region of the PLCE1 gene. Analysis was repeated on DNA samples from repeated blood and saliva samples.

Results: SNP analysis revealed two long regions of homozygosity on chromosomes 10 and 13. One of these contained the PLCE1 gene (sometimes known as KIAA1516, PLCE or NPHS3) recently described as a cause of DMS. All affected children were homozygous for a four base-pair deletion in exon 3, which creates a premature translational stop codon. However, analysis of the asymptomatic father of two of the children revealed that he was homozygous for the same mutation. This result was confirmed using a variety of PCR primers and MLPA. Methylation analysis revealed normal biparental inheritance of chromosome 10. Microsatellite analysis …