PubMed · 1699208
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H Y Zoghbi, A E McCall. 1990-10-11. BclI and MspI polymorphisms at the D6S90 locus.. https://doi.org/10.1093/nar%2F18.19.5922
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Juvenile myoclonic epilepsy (JME) is a distinct form of idiopathic generalized epilepsy (IGE). One of the candidate regions for human JME has been mapped on chromosome band 6p11-p12 by linkage analyses and is termed EJM1 (MIM 254770). Recently, we reported the reduction of the EJM1 region to 3.5cM that contains 18 genes, the exclusion of three genes (LRRC1, GCLC, KIAA0057) by mutation analyses, and the identification of Myoclonin1/EFHC1 as the EJM1 gene. Here, we describe detailed physical and transcriptome maps of the 3.5cM EJM1 region, and detailed results of mutation analyses for the remained 14 genes (HELO1, GCMA, KIAA0936, FBXO9, GSTA3, GSTA4, PTD011, KIAA0576, LMPB1, IL17F, MCM3, PKHD1, KIAA0105, TFAP2B) in patients with JME. We identified 49 single nucleotide changes in eight genes. Twelve amino acid substitutions occurred in two genes, 11 silent mutations in seven genes, and 26 in the non-coding or intronic regions of seven genes. Twelve amino acid substitutions in the two genes (IL17F, PKHD1) were also observed in healthy control individuals or did not co-segregate with the disease phenotypes in other family members. Thus, the absence of significant and potentially functional mutations in the remaining 14 genes further supports the concept that Myoclonin1/EFHC1 is the EJM1 gene in chromosome 6p12.
Autosomal recessive polycystic kidney disease (ARPKD) belongs to a group of congenital hepatorenal fibrocystic syndromes characterized by dual renal and hepatic involvement of variable severity. Despite the wide clinical spectrum of ARPKD (MIM 263200), genetic linkage studies indicate that mutations at a single locus, PKHD1 (polycystic kidney and hepatic disease 1), located on human chromosome region 6p21.1-p12, are responsible for all phenotypes of ARPKD. Identification of cystic disease genes and their encoded proteins has provided investigators with critical tools to begin to unravel the molecular and cellular mechanisms of PKD. PKD cystic epithelia share common phenotypic abnormalities despite the different genetic mutations that underlie the disease. Recent studies have shown that many cyst-causing proteins are expressed in multimeric complexes at distinct subcellular locations within epithelia. This co-expression of cystoproteins suggests that cyst formation, regardless of the underlying disease gene, results from perturbations in convergent and/or integrated signal transduction pathways. To date, no specific therapies are in clinical use for ameliorating cyst growth in ARPKD. However, studies noted in this review suggest that therapeutic targeting of the cAMP and epidermal growth factor receptor (EGFR)-axis abnormalities in cystic epithelia may translate into effective therapies for ARPKD and, by analogy, autosomal dominant polycystic kidney disease (ADPKD). A particularly promising approach appears to be the targeting of downstream intermediates of both the cAMP and EGFR axis. This review focuses on ARPKD and presents a concise summary of the current understanding of the molecular genetics and cellular pathophysiology of this disease. It also highlights phenotypic and mechanistic similarities between ARPKD and ADPKD.
Trisomy 6 is seen in early miscarriages in association with an intact, empty amniotic sac or as a pseudomosaic in amniotic fluid cultures. We report the finding of mosaic trisomy 6 in a 23-week-gestation pregnancy terminated because of intrauterine death. The post-mortem showed a well formed macerated male fetus with an atrioventricular septal defect and an exomphalos. By conventional cytogenetics, trisomy 6 was found in 12 out of 25 (48%) fibroblast colonies from fetal skin and 21 out of 32 (66%) colonies derived from amnion, while the remaining metaphases showed an apparently normal male karyotype. Molecular genetic studies on DNA from uncultured fetal skin and cord samples using polymorphic microsatellite repeat sequences showed no evidence of trisomy 6, but demonstrated that both chromosome 6 homologs were of maternal origin consistent with maternal uniparental disomy (UPD).