MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability

Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.Peer reviewe

A Family with Vocal Cord Paralysis Associated with GDAP1 Mutation in Giresun, Turkey

WOS: 000372008100012A Turkish family living in northern Turkey with hereditary neuropathy is described herein. The current study presents two sisters with severe proximal and distal motor deficits, anatomic deformities, such as pes cavus and claw hand, dependency on wheelchairs, who were born to parents with fifth-degree consanguinity, and developed vocal cord paralysis in the follow-up. The genetic analysis revealed that the siblings were homozygous for p. Q38X (c. 112C>T) mutation in the GDAP1 gene. There are rare reports of vocal cord paresis in patients with hereditary neuropathy, which may result in respiratory difficulty in the clinical course. The aim of the current study was to highlight the importance of genetic studies that predict the development of vocal cord paralysis, which could reduce the expected life span in patients with hereditary neuropathy, a condition commonly encountered in our region owing to consanguineous marriage

NERVE CONDUCTION STUDIES IN CHARCOT-MARIE-TOOTH DISEASE IN A COHORT FROM TURKEY

Introduction: In the demyelinating form of Charcot-Marie-Tooth disease, median motor conduction velocity (MCV) was noted to be around 20 m/s in peripheral myelin protein 22 (PMP22) duplications, in contrast to higher MCVs in connexin 32 gene (Cx32) mutations and lower MCVs in the demyelinating form of myelin protein zero gene (MPZ) mutations. Methods: Nerve conduction studies were performed in 64 families with both common and rare mutations. Results: Mean MCV of the median nerve was 20 +/- 5 m/s in PMP22 duplications, 34 +/- 6 m/s in Cx32 mutations, 20 +/- 9 m/s in KIAA1985 (SH3TC2) mutations, and 11 +/- 8 m/s in MPZ mutations. Conduction was generally uniform; however, conduction blocks were present in 1 patient each with the MPZ mutation and PMP22 duplication, both with unusual phenotypes. Conclusion: Our results confirm those of the other investigators. Electrophysiological results of the rare KIAA1985 (SH3TC2) mutation reveal that their MCVs span a broad range and that conduction is uniform. Muscle Nerve 43: 657-664, 201

Neonatal Nav1.5 protein expression in normal adult human tissues and breast cancer

Expression of the neonatal splice variant of the voltage-gated sodium channel alpha-subunit (VGSC) subtype Nav1.5 (nNav1.5), encoded by the gene SCN5A, was shown earlier to be upregulated in human breast cancer (BCa), both in vitro and in vivo. Channel activity promoted BCa invasion of Matrigel (R) in vitro and metastasis in vivo. Consequently, expression of nNav1.5 has been proposed as a functional biomarker of BCa cells with metastatic potential. Here, we have determined immunohistochemically both nNav1.5 and total VGSC (tVGSC) protein expression in a range of adult human tissues. Some VGSC protein was expressed in normal colon, small intestine, stomach, prostate, bladder and breast. As expected, high levels of VGSC protein were expressed in brain, skeletal muscle and cardiac muscle. On the other hand, nNav1.5 protein was not expressed in any of the normal tissues tested except breast where a low-level of protein was present. In comparison to normal breast, nNav1.5 protein expression in BCa was consistently widespread and occurred at a significantly higher level. We also questioned whether there was any relationship between the nNav1.5 protein expression and the estrogen receptor (ER alpha) status of BCa and obtained the following results. First, all cases lacking nNav1.5 were positive for ERa. SOecond, in all ER alpha-negative tissues, nNav1.5 protein was expressed in plasma membrane. Third, however, in ER alpha-positive cases, nNav1.5 protein expression was observed in both plasma membrane and cytoplasm. In conclusion, nNav1.5 protein has a restricted expression pattern among human tissues. High level expression occurs in BCa and associates with ERa status. These results further support the proposition that nNav1.5 is a novel biomarker of metastatic BCa. (C) 2017 Elsevier GmbH. All rights reserved

Challenging the Western stereotype : do Chinese international foundation students learn by rote?

The dissonance between Eastern and Western learning approaches is regarded as an obstacle for Chinese students in adjusting to Western education environments, and one of the reasons is the lack of an understanding of Chinese learning approaches, that is, Chinese learners are uncritically perceived as rote learners. This paper investigates Chinese international foundation students’ learning approaches when they were in China and here in the UK. Their experiences indicate that, similarly to UK students, Chinese students learn with the intention of understanding, they use memorisation only when they fail to understand or have examination pressure. Consequently, Chinese students adjust well to Western teaching styles. Some difficulties they experienced in classrooms are due to language problems and a lack of understanding of Western cultural backgrounds and expectations. Moreover, similarly to UK students who leave home for the first time, the greatest challenge is to develop self-regulated learning. The paper argues that, although Eastern and Western teaching styles are significantly different, students’ underlying learning approaches can be similar in China and the West