Porokeratosis (PK) is a heterogeneous group of keratinization disorders. No causal genes except MVK have been identified, even though the disease was linked to several genomic loci. Here, we performed massively parallel sequencing and exonic CNV screening of 12 isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway. Allelic expression imbalance (AEI) assays were performed in 13 lesional tissues. At least one mutation in one of the four genes in the mevalonate pathway was found in 60 (98%) familial and 53 (73%) sporadic patients, which suggests that isoprenoid biosynthesis via the mevalonate pathway may play a role in the pathogenesis of PK. Significantly reduced expression of the wild allele was common in lesional tissues due to gene conversion or some other unknown mechanism. A G-to-A RNA editing was observed in one lesional tissue without AEI. In addition, we observed correlations between the mutations in the four mevalonate pathway genes and clinical manifestations in the PK patients, which might support a new and simplified classification of PK under the guidance of genetic testing.DOI: http://dx.doi.org/10.7554/eLife.06322.001
Familial cortical myoclonic tremor with epilepsy is an autosomal dominant neurodegenerative disease, characterized by cortical tremor and epileptic seizures. Although four subtypes (types 1-4) mapped on different chromosomes (8q24, 2p11.1-q12.2, 5p15.31-p15.1 and 3q26.32-3q28) have been reported, the causative gene has not yet been identified. Here, we report the genetic study in a cohort of 20 Chinese pedigrees with familial cortical myoclonic tremor with epilepsy. Linkage and haplotype analysis in 11 pedigrees revealed maximum two-point logarithm of the odds (LOD) scores from 1.64 to 3.77 (LOD scores in five pedigrees were >3.0) in chromosomal region 8q24 and narrowed the candidate region to an interval of 4.9 Mb. Using whole-genome sequencing, long-range polymerase chain reaction and repeat-primed polymerase chain reaction, we identified an intronic pentanucleotide (TTTCA)n insertion in the SAMD12 gene as the cause, which co-segregated with the disease among the 11 pedigrees mapped on 8q24 and additional seven unmapped pedigrees. Only two pedigrees did not contain the (TTTCA)n insertion. Repeat-primed polymerase chain reaction revealed that the sizes of (TTTCA)n insertion in all affected members were larger than 105 repeats. The same pentanucleotide insertion (ATTTCATTTC)58 has been reported to form RNA foci resulting in neurotoxicity in spinocerebellar ataxia type 37, which suggests the similar pathogenic process in familial cortical myoclonic tremor with epilepsy type 1.
Interindividual differences in human CYP1A1 and CYP1A2 expression appear to be associated with variability in risk toward various types of environmental toxicity and cancer. These two genes are oriented head-to-head on human chromosome 15; the 23.3-kb spacer region might contain distinct regulatory regions for CYP1A1 and distinct regulatory regions for CYP1A2, or the regulatory regions for the two genes might overlap one another. From 24 unrelated subjects of five major, geographically-isolated subgroups, we resequenced both genes (all exons and all introns) plus some 3' flanking sequences and the entire spacer region (39.6 kb total); 85 SNPs were found, 49 of which were not currently in the National Center for Biotechnology Information (NCBI) database. Of the 57 double-hit SNPs, we carried out SNP-typing in 94 Africans, 96 Asians, and 83 Caucasians and found striking ethnic differences in SNP frequencies and haplotype evolution; the two CYP1A1 SNPs and the one CYP1A2 SNP that are most commonly used in epidemiological studies were shown not to be representative haplotype tag SNPs across these three human subgroups. Four BAC-transgenic mouse lines, carrying the human CYP1A2 and 15,190 bp of 5' flank, expressed only negligible basal or inducible CYP1A2 mRNA. A fifth BAC-transgenic mouse line, carrying both the human CYP1A1 and CYP1A2 genes and ample amounts of 3' flanking sequences, plus all of the spacer region--in the absence of the mouse Cyp1a1 or Cyp1a2 genes--expressed the human CYP1A1 and CYP1A2 mRNA, protein and enzyme activities in liver and nonhepatic tissues very similar to that of the mouse. Comparison of this hCYP1A1_1A2 transgenic line with hCYP1A1_1A2 lines carrying other common human haplotypes will enable us to evaluate function in human CYP1A1_CYP1A2 locus variability, with regard to toxicity and cancer caused by combustion products.
The genotype responsible for more than 60-fold interindividual differences in human hepatic CYP1A2 constitutive expression is not understood. Resequencing the human CYP1A1_CYP1A2 locus (39.6 kb) in five major geographically isolated subgroups recently led to the identification of 85 single nucleotide polymorphisms (SNPs), 57 of which were double-hit SNPs. Here, we attempted to correlate the CYP1A2 genotype with a metabolic phenotype. We chose 16 SNPs (all having a minor allele frequency > or =0.05 in Caucasians) to genotype 32 DNA samples (26 Caucasians, six Ethiopians) in which CYP1A2 metabolism had previously been determined. From 280 subjects (five locations worldwide) that had been CYP1A2-phenotyped, we genotyped the 10 highest, 14 lowest and eight intermediate DNA samples. Although no SNP was significant (P<0.05), possibly due to the small sample size, we found a trend for several of the six SNPs across the CYP1A2 linkage disequilibrium block associated with the trait. Five CYP1A2 haplotypes were inferred, two of which had not previously been reported; haplotype 1A2H10 showed the greatest association with CYP1A2 activity. Regulatory sequences responsible for the large interindividual differences in hepatic CYP1A2 gene basal expression might reside, in part, with some of these CYP1A2 SNPS but, in large part, might be located either cis (in nearby sequences not yet haplotyped) or trans in that they are not linked to the gene. We conclude that no SNP or haplotype in the CYP1A2 gene has yet been identified that can unequivocally be used to predict the metabolic phenotype in any individual patient.
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