Identification of a novel heterozygous mutation in the MITF gene in an Iranian family with Waardenburg syndrome type II using next-generation sequencing.

BACKGROUND: Waardenburg syndrome (WS) is a genetically heterogeneous syndrome with both autosomal recessive and dominant inheritance. WS causes skin and iris pigmentation accumulation and sensorineural hearing loss, in varying degrees. There are four WS types with different characteristics. WS1 and WS2 are the most common and have a dominant inheritance. WS2 is caused by mutations in the microphthalmia-associated transcription factor (MITF) gene. METHODS: An Iranian couple with hearing loss was recruited in the present study. First, they were screened for GJB2 and GJB6 gene mutations, and then whole-exome sequencing 100X was performed along with bioinformatics analysis. RESULTS: A novel pathogenic heterozygous mutation, c.425T>A; p.L142Ter, was detected in the MITF gene's exon 4. Bioinformatics analysis predicted c.425T>A; p.L142Ter as a possible pathogenic variation. It appears that the mutated transcript level declines through nonsense-mediated decay. It probably created a significantly truncated protein and lost conserved and functional domains like basic helix-loop-helix-zipper proteins. Besides, the variant was utterly co-segregated with the disease within the family. CONCLUSIONS: We investigated an Iranian family with congenital hearing loss and identified a novel pathogenic variant c.425T>A; p. L142Ter in the MITF gene related to WS2. This variant is a nonsense mutation, probably leading to a premature stop codon. Our data may be beneficial in upgrading gene mutation databases and identifying WS2 causes.

Identification of the PRM1 gene mutations in oligoasthenoteratozoospermic men.

Mutations or altered expression of PRM1 gene have been associated with male infertility. This study aimed to analyse pathogenic variations of PRM1 gene in Iranian Arab infertile men with oligoasthenoteratozoospermia that was carried out for the first time in this population. Genomic DNA was used to perform PCR sequencing in PRM1 untranslated regions, exons and intron. Also, bioinformatics analysis was recruited to discover the possible effect of detected variations. Two pathogenic variations were seen in two men with oligoasthenoteratozoospermia, which were not found in the control group. The cDNA.384G>C variation is novel and was located in the 3' untranslated region, and cDNA.42G>A variation is reported for the first time related to male infertility and was found in 5' untranslated regions. Bioinformatics analysis showed that the minimum free energy was increased from -19.9kcal/mol to -13.1kcal/mol due to the cDNA.384G>C variation at hsa-miR-4326's seed site. More analysis revealed cDNA.42G>A located in transcription factors binding site, E1 and MYOD, which was detected as a promoter-associated region, and generally have regulatory features for acetylation and methylation. In conclusion, two pathogenic variations were recognised in regulatory areas of PRM1 gene, which might interfere with some critical factors related to PRM1 gene expression, hence cause male infertility.