Low incidence of limb-girdle muscular dystrophy type 2C revealed by a mutation study in Japanese patients clinically diagnosed with DMD

<p>Abstract</p> <p>Background</p> <p>Limb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive muscle dystrophy that resembles Duchenne muscular dystrophy (DMD). Although DMD is known to affect one in every 3500 males regardless of race, a widespread founder mutation causing LGMD2C has been described in North Africa. However, the incidence of LGMD2C in Japanese has been unknown because the genetic background remains uncharacterized in many patients clinically diagnosed with DMD.</p> <p>Methods</p> <p>We enrolled 324 patients referred to the Kobe University Hospital with suspected DMD. Mutations in the dystrophin or the SGCG genes were analyzed using not only genomic DNA but also cDNA.</p> <p>Results</p> <p>In 322 of the 324 patients, responsible mutations in the dystrophin were successfully revealed, confirming DMD diagnosis. The remaining two patients had normal dystrophin expression but absence of γ-sarcoglycan in skeletal muscle. Mutation analysis of the SGCG gene revealed homozygous deletion of exon 6 in one patient, while the other had a novel single nucleotide insertion in exon 7 in one allele and deletion of exon 6 in the other allele. These mutations created a stop codon that led to a γ-sarcoglycan deficiency, and we therefore diagnosed these two patients as having LGMD2C. Thus, the relative incidence of LGMD2C among Japanese DMD-like patients can be calculated as 1 in 161 patients suspected to have DMD (2 of 324 patients = 0.6%). Taking into consideration the DMD incidence for the overall population (1/3,500 males), the incidence of LGMD2C can be estimated as 1 per 560,000 or 1.8 per million.</p> <p>Conclusions</p> <p>To the best of our knowledge, this is the first study to demonstrate a low incidence of LGMD2C in the Japanese population.</p

Chapter 3: Pathophysiology

The hallmark pathophysiologic feature of dilated cardiomyopathy is systolic dysfunction. Several pathogenetic mechanisms appear to be operative. These include increased hemodynamic overload, ventricular remodeling, excessive neurohumoral stimulation, abnormal myocyte calcium cycling, excessive or inadequate proliferation of the extracellular matrix, accelerated apoptosis, and genetic mutations. Although beneficial in the early stages of heart failure, these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. Genetic causes account for 30\u201340% of DCM and involve genes that encode a heterogeneous group of molecules that participate in force generation, force transmission, sarcomere integrity, cytoskeletal and nuclear architecture, electrolyte homeostasis, mitochondrial function, and transcription. Additional research will improve our understanding of the complex and longitudinal molecular changes that lead from gene mutation to clinical expressio

Lamin A/C truncation in dilated cardiomyopathy with conduction disease

BACKGROUND: Mutations in the gene encoding the nuclear membrane protein lamin A/C have been associated with at least 7 distinct diseases including autosomal dominant dilated cardiomyopathy with conduction system disease, autosomal dominant and recessive Emery Dreifuss Muscular Dystrophy, limb girdle muscular dystrophy type 1B, autosomal recessive type 2 Charcot Marie Tooth, mandibuloacral dysplasia, familial partial lipodystrophy and Hutchinson-Gilford progeria. METHODS: We used mutation detection to evaluate the lamin A/C gene in a 45 year-old woman with familial dilated cardiomyopathy and conduction system disease whose family has been well characterized for this phenotype [1]. RESULTS: DNA from the proband was analyzed, and a novel 2 base-pair deletion c.908_909delCT in LMNA was identified. CONCLUSIONS: Mutations in the gene encoding lamin A/C can lead to significant cardiac conduction system disease that can be successfully treated with pacemakers and/or defibrillators. Genetic screening can help assess risk for arrhythmia and need for device implantation

Two novel missense mutations in the myostatin gene identified in Japanese patients with Duchenne muscular dystrophy

BACKGROUND: Myostatin is a negative regulator of skeletal muscle growth. Truncating mutations in the myostatin gene have been reported to result in gross muscle hypertrophy. Duchenne muscular dystrophy (DMD), the most common lethal muscle wasting disease, is a result of an absence of muscle dystrophin. Although this disorder causes a rather uniform pattern of muscle wasting, afflicted patients display phenotypic variability. We hypothesized that genetic variation in myostatin is a modifier of the DMD phenotype. METHODS: We analyzed 102 Japanese DMD patients for mutations in the myostatin gene. RESULTS: Two polymorphisms that are commonly observed in Western countries, p.55A>T and p.153K>R, were not observed in these Japanese patients. An uncommon polymorphism of p.164E>K was uncovered in four cases; each patient was found to be heterozygous for this polymorphism, which had the highest frequency of the polymorphism observed in the Japanese patients. Remarkably, two patients were found to be heterozygous for one of two novel missense mutations (p.95D>H and p.156L>I). One DMD patient carrying a novel missense mutation of p.95D>H was not phenotypically different from the non-carriers. The other DMD patient was found to carry both a novel mutation (p.156L>I) and a known polymorphism (p.164E>K) in one allele, although his phenotype was not significantly modified. Any nucleotide change creating a target site for micro RNAs was not disclosed in the 3' untranslated region. CONCLUSION: Our results indicate that heterozygous missense mutations including two novel mutations did not produce an apparent increase in muscle strength in Japanese DMD cases, even in a patient carrying two missense mutations

A steric tethering approach enables palladium-catalysed C-H activation of primary amino alcohols.

Aliphatic primary amines are a class of chemical feedstock essential to the synthesis of higher-order nitrogen-containing molecules, commonly found in biologically active compounds and pharmaceutical agents. New methods for the construction of complex amines remain a continuous challenge to synthetic chemists. Here, we outline a general palladium-catalysed strategy for the functionalization of aliphatic C-H bonds within amino alcohols, an important class of small molecule. Central to this strategy is the temporary conversion of catalytically incompatible primary amino alcohols into hindered secondary amines that are capable of undergoing a sterically promoted palladium-catalysed C-H activation. Furthermore, a hydrogen bond between amine and catalyst intensifies interactions around the palladium and orients the aliphatic amine substituents in an ideal geometry for C-H activation. This catalytic method directly transforms simple, easily accessible amines into highly substituted, functionally concentrated and structurally diverse products, and can streamline the synthesis of biologically important amine-containing molecules.We are grateful to the Marie Curie Foundation (D.P. & J.C.), EPSRC (T.W.G.), the ERC (V.D.), and the ERC and EPSRC for Fellowships (M.J.G.). We are grateful to Adam Smalley for DFT calculations and Yohei Shimidzu for assistance with optimization of the C–H acetoxylation reaction. Mass spectrometry data was acquired at the EPSRC UK National Mass Spectrometry Facility at Swansea University. The authors declare no competing financial interests.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nchem.236

Health disparities by occupation, modified by education: a cross-sectional population study

<p>Abstract</p> <p>Background</p> <p>Socio-economic disparities in health status are frequently reported in research. By comparison with education and income, occupational status has been less extensively studied in relation to health status or the occurrence of specific chronic diseases. The aim of this study was to investigate health disparities in the working population based on occupational position and how they were modified by education.</p> <p>Methods</p> <p>Our data were derived from the National Survey of General Practice that comprised 104 practices in the Netherlands. 136,189 working people aged 25–64 participated in the study. Occupational position was assessed by the International Socio-Economic Index of occupational position (ISEI). Health outcomes were self-perceived health status and physician-diagnosed diseases. Odds ratios were estimated using multivariate logistic regression analysis.</p> <p>Results</p> <p>The lowest occupational position was observed to be associated with poor health in men (OR = 1.6, 95% CI 1,5 to 1.7) and women (OR = 1.3, 95% CI 1.2 to 1.4). The risk of poor health gradually decreased in relation to higher occupational positions. People with the lowest occupational positions were more likely to suffer from depression, diabetes, ischaemic heart disease, arthritis, muscle pain, neck and back pain and tension headache, in comparison to people with the highest occupational position (OR 1.2 to 1.6). A lower educational level induced an additional risk of poor health and disease. We found that gender modified the effects on poor health when both occupational position and education were combined in the analysis.</p> <p>Conclusion</p> <p>A low occupational position was consistently associated working people with poor health and physician-diagnosed morbidity. However a low educational level was not. Occupational position and education had a combined effect on self-perceived health, which supports the recent call to improve the conceptual framework of health disparities.</p

Peripheral nervous system manifestations in a Sandhoff disease mouse model: nerve conduction, myelin structure, lipid analysis

<p>Abstract</p> <p>Background</p> <p>Sandhoff disease is an inherited lysosomal storage disease caused by a mutation in the gene for the β-subunit (<it>Hexb </it>gene) of β-hexosaminidase A (αβ) and B (ββ). The β-subunit together with the GM2 activator protein catabolize ganglioside GM2. This enzyme deficiency results in GM2 accumulation primarily in the central nervous system. To investigate how abnormal GM2 catabolism affects the peripheral nervous system in a mouse model of Sandhoff disease (<it>Hexb-/-</it>), we examined the electrophysiology of dissected sciatic nerves, structure of central and peripheral myelin, and lipid composition of the peripheral nervous system.</p> <p>Results</p> <p>We detected no significant difference in signal impulse conduction velocity or any consistent change in the frequency-dependent conduction slowing and failure between freshly dissected sciatic nerves from the <it>Hexb</it>+/- and <it>Hexb</it>-/- mice. The low-angle x-ray diffraction patterns from freshly dissected sciatic and optic nerves of <it>Hexb</it>+/- and <it>Hexb</it>-/- mice showed normal myelin periods; however, <it>Hexb</it>-/- mice displayed a ~10% decrease in the relative amount of compact optic nerve myelin, which is consistent with the previously established reduction in myelin-enriched lipids (cerebrosides and sulfatides) in brains of <it>Hexb-/- </it>mice. Finally, analysis of lipid composition revealed that GM2 content was present in the sciatic nerve of the <it>Hexb</it>-/- mice (undetectable in <it>Hexb</it>+/-).</p> <p>Conclusion</p> <p>Our findings demonstrate the absence of significant functional, structural, or compositional abnormalities in the peripheral nervous system of the murine model for Sandhoff disease, but do show the potential value of integrating multiple techniques to evaluate myelin structure and function in nervous system disorders.</p