Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis

Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations

Mutations of complement lectin pathway genes MBL2 and MASP2 associated with placental malaria

Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

New susceptibility loci associated with kidney disease in type 1 diabetes

WOS:000309817900008Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.Peer reviewe

On chemical denudation caused by ground water in central Finnish Lapland

In the study an estimate was made of the chemical denudation caused by ground water discharged from surficial deposits, on the basis of the dissolved inorganic matter, during the late and postglacial period of approximately 10 000 years. The calculations are based on the premise that in only a gently sloping, till-mantled tract the infiltration coefficient of the ground water varies between 0.20 and 0.40, and in level tracts covered with sand and gravel between 0.40 and 0.60. Further, the amount of annual precipitation taken into account in the calculations varies from 450 to 500 mm, and the dry unit weights of the till and the stratified drift amount to 1.60 and 1.70 t per cu. m. The assumption was made that the postglacial fluctuations in climatic conditions in one and another direction cancel each other out to the extent that they do not significantly affect the calculations. The appreciable amounts of matter brought down out of the atmosphere by the rain have been taken into account. The chemical denudation caused by ground water percolating through till in areas of silicic bedrock corresponds to the elimination of a soil layer of between 2.0 and 4.5 cm in thickness, the corresponding value in areas of subsilicic bedrock being 5.5 to 11.0 cm. In silicic bedrock areas the chemical denudation is slightly more intensive in stratified drift than in till deposits. Not taking into account the composition of the surficial deposits and the bedrock, the average rate of chemical denudation in the whole study area was found to be from 2.4 to 5.8 cm. This finding is in agreement with the calculations made on the basis of brook and river waters

Origin, mineralogy, and chemistry of manganiferous and ferruginous precipitates found in sand and gravel deposits in Finland

Different types of manganiferous and ferruginous precipitates found in glaciofluvial sediments are described. Mn is enriched into places where oxidizing conditions prevail, probably through chemical processes alone. In moist oxidates the enrichment of Mn originally coprecipitated with Fe continues through the partial dissolution of the precipitated Mn-compounds in interparticle fluids. The only Mn-rich mineral identified through X-ray diffraction of manganiferous cements was birnessite. It precipitates from groundwater instead of pure manganese oxides because of the foreign cations present. Of these, Ca seems to be the most important, while the amount of other cations: Fe, Al, Mg, K, and Na, varies, and is dependent on ithe composition of percolating waters and the state of crystallization. Goethite and lepidocrocite were observed in ferruginous precipitates. Upon heating, birnessite recrystallizes as hausmannite and spinel when few foreign ions are present, and also as bixbyite if the sample contains enough iron. Ferruginous precipitates recrystallize as hematite upon heating. The precipitation of Mn-rich compounds from groundwater in which more Fe than Mn is present is tentatively attributed to the lower stability of Mn-complexes — with organic and -HCO3ligands usually — which within higher pH—Eh decompose in sand and gravel before Fe-complexes do. This leads, under suitable conditions, to the oxidation of Mn2+ in groundwater discharges and in well-aerated sediments. Fe precipitates after Mn because it is complex-bound and does not precipitate before the complex is destroyed, e.g., by organisms

Ferruginous concretions around root channels in clay and fine sand deposits

Spherically layered ferruginous concretions formed in soils in Finland are described. The cementing iron-rich material is in an amorphic state and binds the loose detrital mineral grains of quartz, feldspars, amphiboles, etc. Electron microprobe analyses show that iron and manganese are present as concentric rings around the root channels but that calcium is evenly distributed. The highest manganese content is found near the channel as a dark almost black layer or spot, but around the centre, where the content of cementing materials decreases, iron predominates. The origin of these ferruginous concretions and the significance of redox conditions in soils during their formation are discussed