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1.
Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome 总被引:6,自引:0,他引:6
Windpassinger C Auer-Grumbach M Irobi J Patel H Petek E Hörl G Malli R Reed JA Dierick I Verpoorten N Warner TT Proukakis C Van den Bergh P Verellen C Van Maldergem L Merlini L De Jonghe P Timmerman V Crosby AH Wagner K 《Nature genetics》2004,36(3):271-276
Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration. 相似文献
2.
Steinbusch LK Schwenk RW Ouwens DM Diamant M Glatz JF Luiken JJ 《Cellular and molecular life sciences : CMLS》2011,68(15):2525-2538
Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose
transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored
in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well
as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly
affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized
at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate
uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences
in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved
in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both
GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking
components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development
of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy. 相似文献
3.
Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. 总被引:20,自引:0,他引:20
Antoine H F M Peters Jacqueline E Mermoud Dónal O'Carroll Michaela Pagani Dieter Schweizer Neil Brockdorff Thomas Jenuwein 《Nature genetics》2002,30(1):77-80
Post-translational modifications of histone amino termini are an important regulatory mechanism that induce transitions in chromatin structure, thereby contributing to epigenetic gene control and the assembly of specialized chromosomal subdomains. Methylation of histone H3 at lysine 9 (H3-Lys9) by site-specific histone methyltransferases (Suv39h HMTases) marks constitutive heterochromatin. Here, we show that H3-Lys9 methylation also occurs in facultative heterochromatin of the inactive X chromosome (Xi) in female mammals. H3-Lys9 methylation is retained through mitosis, indicating that it might provide an epigenetic imprint for the maintenance of the inactive state. Disruption of the two mouse Suv39h HMTases abolishes H3-Lys9 methylation of constitutive heterochromatin but not that of the Xi. In addition, HP1 proteins, which normally associate with heterochromatin, do not accumulate with the Xi. These observations suggest the existence of an Suv39h-HP1-independent pathway regulating H3-Lys9 methylation of facultative heterochromatin. 相似文献
4.
Loïs Rancilhac Teddy Bruy Mark D. Scherz Elvis Almeida Pereira Michaela Preick Nicolas Straube 《Journal of Natural History》2020,54(1-4):87-118
ABSTRACT The subgenus Mantidactylus is a group of frogs endemic to Madagascar, including the largest anuran species on the island. Although these frogs are common and widely distributed, their taxonomy remains unclear. Two species are currently recognised, M. grandidieri and M. guttulatus, with another available name, Rana pigra, considered to be a synonym of M. grandidieri. However, molecular studies have suggested the presence of several cryptic species within the group. Additionally, due to the lack of prominent morphological features, allocating the available names to evolutionary lineages has proven challenging. In the present study, we take a first step towards solving these problems by using fragments of the 16S mitochondrial gene and RAG1 nuclear gene from all over the range of the subgenus to describe its genetic diversity. We also use a newly designed target enrichment laboratory protocol to sequence three mitochondrial fragments from five name-holding museum specimens (as old as 120 years) in order to determine to which lineages the existing names should be applied. The study of the 16S mitochondrial gene revealed 7 geographically separated lineages, distinct enough to be considered candidate species. Out of the five museum specimens analysed, four successfully yielded DNA sequences and could be attributed to one of the aforementioned lineages. Therefore, the name Mantidactylus grandidieri should be applied to the populations from North-Eastern Madagascar, while M. guttulatus refers to populations from inland localities along the Eastern coast of the island. On the other hand, the holotype of Rana pigra did not yield enough genetic material to allow definitive identification. While our data were not sufficient to assess the status of the four lineages distributed along the Eastern coast, the populations from North-Western Madagascar were highly distinct on both the mitochondrial and nuclear markers. We thus describe them as a new species, M. radaka sp. nov. http://www.zoobank.org/urn:lsid:zoobank.org:pub:1EDDAF0D-FE37-490A-B09E-E136A0C5CB35 相似文献
5.
TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity 总被引:2,自引:0,他引:2
Gack MU Shin YC Joo CH Urano T Liang C Sun L Takeuchi O Akira S Chen Z Inoue S Jung JU 《Nature》2007,446(7138):916-920
Retinoic-acid-inducible gene-I (RIG-I; also called DDX58) is a cytosolic viral RNA receptor that interacts with MAVS (also called VISA, IPS-1 or Cardif) to induce type I interferon-mediated host protective innate immunity against viral infection. Furthermore, members of the tripartite motif (TRIM) protein family, which contain a cluster of a RING-finger domain, a B box/coiled-coil domain and a SPRY domain, are involved in various cellular processes, including cell proliferation and antiviral activity. Here we report that the amino-terminal caspase recruitment domains (CARDs) of RIG-I undergo robust ubiquitination induced by TRIM25 in mammalian cells. The carboxy-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIG-I; this interaction effectively delivers the Lys 63-linked ubiquitin moiety to the N-terminal CARDs of RIG-I, resulting in a marked increase in RIG-I downstream signalling activity. The Lys 172 residue of RIG-I is critical for efficient TRIM25-mediated ubiquitination and for MAVS binding, as well as the ability of RIG-I to induce antiviral signal transduction. Furthermore, gene targeting demonstrates that TRIM25 is essential not only for RIG-I ubiquitination but also for RIG-I-mediated interferon- production and antiviral activity in response to RNA virus infection. Thus, we demonstrate that TRIM25 E3 ubiquitin ligase induces the Lys 63-linked ubiquitination of RIG-I, which is crucial for the cytosolic RIG-I signalling pathway to elicit host antiviral innate immunity. 相似文献
6.
Synaesthesia is the involuntary physical experience of a cross-modal linkage--for example, hearing a tone (the inducing stimulus) evokes an additional sensation of seeing a colour (concurrent perception). Of the different types of synaesthesia, most have colour as the concurrent perception, with concurrent perceptions of smell or taste being rare. Here we describe the case of a musician who experiences different tastes in response to hearing different musical tone intervals, and who makes use of her synaesthetic sensations in the complex task of tone-interval identification. To our knowledge, this combination of inducing stimulus and concurrent perception has not been described before. 相似文献
7.
Weavers H Prieto-Sánchez S Grawe F Garcia-López A Artero R Wilsch-Bräuninger M Ruiz-Gómez M Skaer H Denholm B 《Nature》2009,457(7227):322-326
The nephron is the basic structural and functional unit of the vertebrate kidney. It is composed of a glomerulus, the site of ultrafiltration, and a renal tubule, along which the filtrate is modified. Although widely regarded as a vertebrate adaptation, 'nephron-like' features can be found in the excretory systems of many invertebrates, raising the possibility that components of the vertebrate excretory system were inherited from their invertebrate ancestors. Here we show that the insect nephrocyte has remarkable anatomical, molecular and functional similarity to the glomerular podocyte, a cell in the vertebrate kidney that forms the main size-selective barrier as blood is ultrafiltered to make urine. In particular, both cell types possess a specialized filtration diaphragm, known as the slit diaphragm in podocytes or the nephrocyte diaphragm in nephrocytes. We find that fly (Drosophila melanogaster) orthologues of the major constituents of the slit diaphragm, including nephrin, NEPH1 (also known as KIRREL), CD2AP, ZO-1 (TJP1) and podocin, are expressed in the nephrocyte and form a complex of interacting proteins that closely mirrors the vertebrate slit diaphragm complex. Furthermore, we find that the nephrocyte diaphragm is completely lost in flies lacking the orthologues of nephrin or NEPH1-a phenotype resembling loss of the slit diaphragm in the absence of either nephrin (as in human congenital nephrotic syndrome of the Finnish type, NPHS1) or NEPH1. These changes markedly impair filtration function in the nephrocyte. The similarities we describe between invertebrate nephrocytes and vertebrate podocytes provide evidence suggesting that the two cell types are evolutionarily related, and establish the nephrocyte as a simple model in which to study podocyte biology and podocyte-associated diseases. 相似文献
8.
Lisa Seipold Hermann Altmeppen Tomas Koudelka Andreas Tholey Petr Kasparek Radislav Sedlacek Michaela Schweizer Julia Bär Marina Mikhaylova Markus Glatzel Paul Saftig 《Cellular and molecular life sciences : CMLS》2018,75(17):3251-3267
A disintegrin and metalloproteinase 10 (ADAM10) plays a major role in the ectodomain shedding of important surface molecules with physiological and pathological relevance including the amyloid precursor protein (APP), the cellular prion protein, and different cadherins. Despite its therapeutic potential, there is still a considerable lack of knowledge how this protease is regulated. We have previously identified tetraspanin15 (Tspan15) as a member of the TspanC8 family to specifically associate with ADAM10. Cell-based overexpression experiments revealed that this binding affected the maturation process and surface expression of the protease. Our current study shows that Tspan15 is abundantly expressed in mouse brain, where it specifically interacts with endogenous ADAM10. Tspan15 knockout mice did not reveal an overt phenotype but showed a pronounced decrease of the active and mature form of ADAM10, an effect which augmented with aging. The decreased expression of active ADAM10 correlated with an age-dependent reduced shedding of neuronal (N)-cadherin and the cellular prion protein. APP α-secretase cleavage and the expression of Notch-dependent genes were not affected by the loss of Tspan15, which is consistent with the hypothesis that different TspanC8s cause ADAM10 to preferentially cleave particular substrates. Analyzing spine morphology revealed no obvious differences between Tspan15 knockout and wild-type mice. However, Tspan15 expression was elevated in brains of an Alzheimer’s disease mouse model and of patients, suggesting that upregulation of Tspan15 expression reflects a cellular response in a disease state. In conclusion, our data show that Tspan15 and most likely also other members of the TspanC8 family are central modulators of ADAM10-mediated ectodomain shedding in vivo. 相似文献
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10.
Jo-Anne Chan Katherine B. Howell Christine Langer Alexander G. Maier Wina Hasang Stephen J. Rogerson Michaela Petter Joanne Chesson Danielle I. Stanisic Michael F. Duffy Brian M. Cooke Peter M. Siba Ivo Mueller Peter C. Bull Kevin Marsh Freya J.I. Fowkes James G. Beeson 《Cellular and molecular life sciences : CMLS》2016,73(21):4141-4158