MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion

The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral (OMIM 251880). Known mutant genes, including TK2, SUCLA2, DGUOK and POLG, account for only a fraction of MDDS cases. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17. We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17-/- mice.     

Colligation in modelling practices: From Whewell’s tides to the San Francisco Bay Model

“Colligation”, a term first introduced in philosophy of science by William Whewell (1840), today sparks a renewed interest beyond Whewell scholarship. In this paper, we argue that adopting the notion of colligation in current debates in philosophy of science can contribute to our understanding of scientific models. Specifically, studying colligation allows us to have a better grasp of how integrating diverse model components (empirical data, theory, useful idealization, visual and other representational resources) in a creative way may produce novel generalizations about the phenomenon investigated. Our argument is built both on the theoretical appraisal of Whewell’s philosophy of science and the historical rehabilitation of his scientific work on tides. Adopting a philosophy of science in practice perspective, we show how colligation emerged from Whewell’s empirical work on tides. The production of idealized maps (“cotidal maps”) illustrates the unifying and creative power of the activity of colligating in scientific practice. We show the importance of colligation in modelling practices more generally by looking at its epistemic role in the construction of the San Francisco Bay Model.     

Terrestrial isopods from the Oued Laou basin,north-eastern Morocco (Crustacea: Oniscidea), with descriptions of two new genera and seven new species

Thirty-four species of terrestrial isopods (Crustacea: Oniscidea) from the Oued Laou basin, in the Rif area of north-eastern Morocco, are recorded. One genus (Paractenoscia) and seven species (Trichoniscus microphthalmus, Paractenoscia cavernicola, Bathytropa rifensis, Soteriscus gibbosus, S. laouensis, Porcellio pseudornatus, and Eluma praticola) are described as new. The genus Soteriscus, unavailable according to article 13.3 of the International Commission on Zoological Nomenclature (ICZN), is here revalidated by choosing S. gaditanus as type species. Six species (Graeconiscus thermophilus, Ctenoscia minima, Platyarthrus parisii, Porcellio humberti, Porcellio flavocinctus and Eluma caelata) have been fully illustrated to facilitate their identifications. Ctenoscia dorsalis Verhoeff is considered to be a junior synonym of C. minima Dollfus. Porcellio ornatus from southern Spain is also figured for comparison with P. pseudornatus sp. nov. The composition and origin of the oniscidean fauna of the Rif region is briefly discussed.

http://zoobank.org/urn:lsid:zoobank.org:pub:DCBF3103-1463-4A32-9BC0-A4CFE8B762AE     

Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome

Nevus sebaceous is a common congenital cutaneous malformation. Affected individuals may develop benign and malignant secondary tumors in the nevi during life. Schimmelpenning syndrome is characterized by the association of nevus sebaceous with extracutaneous abnormalities. We report that of 65 sebaceous nevi studied, 62 (95%) had mutations in the HRAS gene and 3 (5%) had mutations in the KRAS gene. The HRAS c.37G>C mutation, which results in a p.Gly13Arg substitution, was present in 91% of lesions. Nonlesional tissues from 18 individuals had a wild-type sequence, confirming genetic mosaicism. The HRAS c.37G>C mutation was also found in 8 of 8 associated secondary tumors. Mosaicism for HRAS c.37G>C and KRAS c.35G>A mutations was found in two individuals with Schimmelpenning syndrome. Functional analysis of HRAS c.37G>C mutant cells showed constitutive activation of the MAPK and PI3K-Akt signaling pathways. Our results indicate that nevus sebaceous and Schimmelpenning syndrome are caused by postzygotic HRAS and KRAS mutations. These mutations may predispose individuals to the development of secondary tumors in nevus sebaceous.     

Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes

Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT(2)) increase type 2 diabetes (T2D) risk(1,2). Although the strongest association signal was highly significant (P < 1 × 10(-20)), its contribution to T2D risk was modest (odds ratio (OR) of ～1.10-1.15)(1-3). We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) <0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78-6.18; P = 1.64 × 10(-4)). A four-tiered functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial- or total-loss-of-function variants but not the neutral ones contributed to T2D (OR = 5.67, CI = 2.17-14.82; P = 4.09 × 10(-4)). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (8,153 individuals with T2D and 10,100 controls; OR = 3.88, CI = 1.49-10.07; P = 5.37 × 10(-3)). This study establishes a firm functional link between MTNR1B and T2D risk.