PMC:4419340 / 11529-14190 JSONTXT

{"project":"2_test","denotations":[{"id":"25918342-23509278-59633018","span":{"begin":506,"end":510},"obj":"23509278"}],"text":"Homozygous nonsense mutations of IL17RC\nWES revealed the presence of different homozygous nonsense mutations of IL17RC in these patients. We chose to investigate these mutations further as potential disease-causing mutations because of their likely impact on IL-17 immunity. In addition, IL17RC displayed a very short biological distance between the known CMCD-causing genes IL17RA and ACT1 (P-values of 0.0005 and 0.0007, respectively), making it a very likely novel candidate gene for CMCD (Itan et al., 2013). P1 was found to be homozygous for the c.412C\u003eT nonsense mutation in exon 3 of the IL17RC gene. This mutation replaces the glutamine codon at position 138 with a premature stop codon (Q138*; Fig. 1 B). The healthy parents, tested siblings, and children of P1 were all heterozygous (WT/Q138*) for the mutant allele, consistent with AR inheritance for this trait (Fig. 1 A). P2 was found to be homozygous for the c.1126C\u003eT nonsense mutation in exon 11 of the IL17RC gene. This mutation replaces the arginine codon in position 376 with a premature stop codon (R376*; Fig. 1 B). The parents and sister of P2 are healthy and heterozygous for the mutant allele, consistent with AR inheritance (Fig. 1 A). P3 was found to be homozygous for the c.1132C\u003eT nonsense mutation in exon 11 of the IL17RC gene, replacing the arginine codon in position 378 with a premature stop codon (R378*; Fig. 1 B). The parents and sister of P3 are healthy and heterozygous for the mutant allele, consistent with AR inheritance (Fig. 1 A). The mutant allele (Q138*) from P1 was not found in any of the various public databases (Human Gene Mutation Database, Ensembl, NHLBI GO Exome Sequencing Project [ESP], 1000 Genomes Project, and the Exome Aggregation Consortium [ExAC]) or in our in-house WES database (∼1,800 exomes), ruling out the possibility of an irrelevant polymorphism and suggesting that this mutation may define a rare AR CMCD-causing allele. The R376* mutant allele, found in P2, has been reported in the ExAC database, only at the heterozygous state, in 5 out of 59,269 individuals. The R378* mutant allele found in P3 has been reported previously (dbSNP accession no. rs143600903), but with a low frequency (0.057%); only one European from a population of 59,318 individuals has been found to be homozygous for this variant, consistent with the notion that this mutation may define a rare AR CMCD-causing allele. The three premature stop codons are located upstream from the segment encoding the transmembrane domain of IL-17RC (Fig. 1 B). No rare coding mutations were found in STAT1, IL17RA, IL17A, IL17F, ACT1, IL22, or IL22RA1 by WES in the three patients."}