Meckel syndrome (MKS) is a severe fetal developmental disorder reported in most populations. The clinical hallmarks are occipital meningoencephalocele, cystic kidney dysplasia, fibrotic changes of the liver and polydactyly. Here we report the identification of a gene, MKS1, mutated in MKS families linked to 17q. Mks1 expression in mouse embryos, as determined by in situ hybridization, agrees well with the tissue phenotype of MKS. Comparative genomics and proteomics data implicate MKS1 in ciliary functions.

Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations (typically occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. MKS is genetically heterogeneous and three loci have been mapped respectively on 17q23 (MKS1), 11q13 (MKS2), and 8q24 (MKS3). Very recently, two genes have been identified: MKS1/FLJ20345 on 17q in Finnish kindreds, carrying the same intronic deletion, c.1408-35_c.1408-7del29, and MKS3/TMEM67 on 8q in families from Pakistan and Oman. Here we report the genotyping of the MKS1 and MKS3 genes in a large, multiethnic cohort of 120 independent cases of MKS. Our first results indicate that the MKS1 and MKS3 genes are each responsible for about 7% of MKS cases with various mutations in different populations. A strong phenotype-genotype correlation, depending on the mutated gene, was observed regarding the type of central nervous system malformation, the frequency of polydactyly, bone dysplasia, and situs inversus. The MKS1 c.1408-35_1408-7del29 intronic mutation was identified in three cases from French or English origin and dated back to 162 generations (approx. 4050 years) ago. We also identified a common MKS3 splice-site mutation, c. INTRODUCTIONMeckel syndrome (MKS; MIM# 249000) is a rare autosomal recessive lethal condition characterized by central nervous system malformations (typically occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia and ductal proliferation in the portal area of the liver (Mecke and Passarge, 1971). Other malformations frequently include microphthalmia, cleft lip and palate, bowing of long bones, heart defects, and genital anomalies, including micropenis. Complete or partial situs inversus and other laterality defects, such as dextrocardia, have been reported in some cases. MKS is genetically heterogeneous and three loci have been mapped on: 17q23 (MKS1) (Paavola, et al., 1995), 11q14 (MKS2) (Roume, et al., 1998), and 8q24 (MKS3) (Morgan, et al., 2002). Very recently, two genes have been identified: MKS1/FLJ20345 (MIM# 609883) on 17q (Kyttälä, et al., 2006) in endogamous Finnish kindreds, and MKS3/TMEM67 (MIM# 607361) on 8q (Smith, et al., 2006) in consanguineous families from Pakistan and Oman. In 26 Finnish families, the same intronic deletion, c.1408-35_1408-7del29 (called the MKS1-Fin major mutation), was found with a common founder haplotype. Comparative genomics and proteomics data have implicated MKS proteins in primary ciliary and basal body function (Kytällä, et al., 2006;Smith, et al., 2006).In order to evaluate the involvement of MKS1 and MKS3 in Meckel syndrome, and to determine phenotypegenotype correlations and the limits of the phenotypes, we sequenced and/or performed denaturing high performance liquid chromatography (dHPLC) WAVE analysis (Transgenomic Inc.) for both MKS1 and MKS3 in a large multiethnic cohort of 120 independent cases of MKS, each diagnosed by experien...

Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.

Objective-Familial combined hyperlipidemia (FCHL) characterized by high serum total cholesterol and/or triglycerides (TGs) is a common dyslipidemia predisposing to coronary artery disease (CAD). Recently, the upstream transcription factor 1 (USF1) was linked and associated with FCHL and TGs in Finnish FCHL families. Here we examined the previously associated rs3737787 SNP in extended Dutch FCHL families (nϭ532) and in a cohort of US subjects who underwent diagnostic coronary angiography (nϭ1533). Methods and Results-In males of the Dutch FCHL families, we observed significant sex-dependent associations between the common allele of rs3737787 and FCHL, TGs, and related metabolic traits (Pϭ0.02 to 0.006). In the U.S. Whites, sex-dependent associations with TGs and related metabolic traits were observed for the common allele of rs3737787 in males (Pϭ0.04 to 0.02) and rare allele in females (Pϭ0.05 to 0.002). This intriguing relationship was further supported by the highly significant genotype x sex interactions observed for TGs in the Dutch and TGs and body mass index (BMI) in U.S. White subjects with CAD (Pϭ0.0005 to 0.00004). Key Words: upstream transcription factor 1 Ⅲ familial combined hyperlipidemia Ⅲ coronary artery disease Ⅲ association Ⅲ lipids F amilial combined hyperlipidemia (FCHL) is a common familial dyslipidemia with a population prevalence of 1% to 2%. 1 Importantly, FCHL is observed in up to 20% of premature coronary artery disease (CAD) patients. 2 In addition to high serum total cholesterol (TC) and triglycerides (TGs), low plasma levels of high-density lipoprotein cholesterol (HDL-C), small dense low-density lipoprotein particles, and elevated apolipoprotein B (apoB) are also often observed in FCHL. 1,2 Association between FCHL and variants of the upstream transcription factor 1 (USF1) located in the FCHL-linked chromosome 1q21 region was originally identified by Pajukanta et al in Finnish FCHL families. 3 Several independent studies have investigated the USF1 variants in samples ascertained for FCHL or risk factors for premature CAD. 2,4 -6 The common allele of rs3737787 or SNPs in linkage disequilibrium (LD) with this SNP were associated with FCHL or one of its component traits in each of these studies. Komulainen et al investigated USF1 variants in a population-based prospective Finnish cohort and observed an association of USF1 with cardiovascular disease and mortality among females, demonstrating a consequence of USF1 at the population level in Finns. 7 In many of these studies, there is evidence of sex specificity, with the common allele of rs3737787 showing strongest evidence for association with high TGs in males. 2,3,7 Interestingly, in females, the minor allele seems to be associated with elevated lipids, as well as cardiovascular disease and mortality. 7 The underlying functional mechanisms explaining this replicated sex specificity are currently unknown. Conclusion-These