Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies

Genetic heterogeneity of motor neuropathies.

OBJECTIVE: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. METHODS: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). RESULTS: The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. CONCLUSIONS: Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies

EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver–Russell and Beckwith–Wiedemann syndrome

Molecular genetic testing for the 11p15-associated imprinting disorders Silver–Russell and Beckwith–Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.net) towards a consensus in diagnostics and management of SRS and BWS, best practice guidelines have now been developed. Members of institutions working in the field of SRS and BWS diagnostics were invited to comment, and in the light of their feedback amendments were made. The final document was ratified in the course of an EMQN best practice guideline meeting and is in accordance with the general SRS and BWS consensus guidelines, which are in preparation. These guidelines are based on the knowledge acquired from peer-reviewed and published data, as well as observations of the authors in their practice. However, these guidelines can only provide a snapshot of current knowledge at the time of manuscript submission and readers are advised to keep up with the literature

De novo missense variants in FBXW11 cause diverse developmental phenotypes including brain, eye and digit anomalies

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include b-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw

Detection of cystic fibrosis mutations in the Greek population

Η ΚΥΣΤΙΚΗ ΙΝΩΔΗΣ ΝΟΣΟΣ ΕΙΝΑΙ ΤΟ ΣΥΧΝΟΤΕΡΟ ΝΟΣΗΜΑ ΤΗΣ ΛΕΥΚΗΣ ΦΥΛΗΣ ΚΑΙ ΚΛΗΡΟΝΟΜΕΙΤΑΙ ΜΕ ΥΠΟΛΕΙΠΟΜΕΝΟ ΣΩΜΑΤΙΚΟ ΧΑΡΑΚΤΗΡΑ.Η ΝΟΣΟΣ ΟΦΕΙΛΕΤΑΙ ΣΤΙΣ ΜΕΤΑΛΛΑΞΕΙΣ ΤΟΥ ΓΟΝΙΔΙΟΥ ΠΟΥ ΕΛΕΓΧΕΙ ΤΗ ΣΥΝΘΕΣΗ ΜΙΑΣ ΜΕΜΒΡΑΝΙΚΗΣ ΠΡΩΤΕΙΝΗΣ ΠΟΥ ΚΑΛΕΙΤΑΙ ''ΡΥΘΜΙΣΤΗΣ ΔΙΑΜΕΜΒΡΑΝΙΚΗΣ ΔΙΑΚΙΝΗΣΗΣ ΙΟΝΤΩΝ'' ΚΑΙ ΛΕΙΤΟΥΡΓΕΙ ΣΑΝ CAMP-ΡΥΘΜΙΖΟΜΕΝΟ ΚΑΝΑΛΙ ΧΛΩΡΙΟΥ.ΓΙΑ ΤΟΝ ΚΑΘΟΡΙΣΜΟ ΤΗΣ ΜΟΡΙΑΚΗΣ ΔΙΑΤΑΡΑΧΗΣΤΗΣ ΝΟΣΟΥ ΣΤΗ ΧΩΡΑ ΜΑΣ ΕΛΕΓΞΑΜΕ 250 ΑΣΘΕΝΕΙΣ ΜΕ ΤΗ ΜΕΘΟΔΟ ΤΗΣ ΚΑΘΕΤΗΣ ΗΛΕΚΤΡΟΦΟΡΗΣΗΣ ΣΕ ΠΗΚΤΩΜΑ ΠΟΛΥΑΚΡΥΛΑΜΙΔΗΣ ΜΕ ΚΛΙΣΗ ΑΠΟΔΙΑΤΑΚΤΙΚΟΥ(DGGE) ΚΑΙ ΑΝΑΛΥΣΗ ΤΗΣ ΑΛΛΗΛΟΥΧΙΑΣ ΤΟΥ DNA (SEQUENCING).ΜΕΤΑ ΑΠΟ ΤΟΝ ΕΛΕΓΧΟ ΚΑΙ ΤΩΝ 27 ΕΞΟΝΙΩΝ ΑΝΙΧΝΕΥΘΗΚΑΝ 54 ΜΕΤΑΛΛΑΞΕΙΣ ΠΟΥ ΚΑΛΥΠΤΟΥΝ ΤΟ 89.8% ΤΩΝ ΠΑΘΟΛΟΓΙΚΩΝ ΧΡΩΜΟΣΩΜΑΤΩΝ.Σ'ΑΥΤΕΣ ΠΕΡΙΛΑΜΒΑΝΟΝΤΑΙ ΚΑΙ 11 ΜΕΤΑΛΛΑΞΕΙΣ ΠΟΥ ΠΕΡΙΓΡΑΦΟΝΤΑΙ ΓΙΑ ΠΡΩΤΗ ΦΟΡΑ ΔΙΕΘΝΩΣ (A46D,296+1G>C,D110E,Y247X,1497 DELGG,E822X,2751+2T>A,2752-26A>G,3153DELT,3272-4A>G, D1445N).H ΔF508 ΑΝΙΧΝΕΥΘΗΚΕ ΣΤΟ 53.6% ΤΩΝ ΠΑΘΟΛΟΓΙΚΩΝ ΧΡΩΜΟΣΩΜΑΤΩΝ, ΕΝΩ ΜΟΝΟ ΑΛΛΕΣ 11 ΜΕΤΑΛΛΑΞΕΙΣ ΑΝΙΧΝΕΥΘΗΚΑΝ ΣΕ ΠΟΣΟΣΤΟ >=1%, ΣΥΜΠΕΡΙΛΑΜΒΑΝΟΜΕΝΗΣ ΚΑΙ ΤΗΣ ΝΕΑΣ ΜΕΤΑΛΛΑΞΗΣ Ε822Χ(1.8%).ΤΟ 10.2% ΤΩΝ ΜΕΤΑΛΛΑΞΕΩΝ ΠΑΡΕΜΕΙΝΕ ΑΔΙΕΥΚΡΙΝΙΣΤΟ.ΕΛΕΓΧΟΣ 7 ΕΞΟΝΙΩΝ ΤΟΥ ΓΟΝΙΔΙΟΥ (10,11,4,21,13,146,176) ΜΕ ΤΗΝ ΤΕΧΝΙΚΗ ΤΟΥ DGGE ΚΑΛΥΠΤΕΙ ΤΟ 80.41% ΤΩΝ ΜΕΤΑΛΛΑΞΕΩΝ.CYSTIC FIBROSIS IS THE MOST COMMON FATAL AUTOSOMAL RECESSIVE DISORDER IN CAUCASIANS , WITH CARRIER FREQUENCY OF APPROXIMATELY 1:20 TO 1:25. THE DISEASE IS CAUSED BY MUTATIONS IN THE GENE CONTROLLING THE SYNTHESIS OF A MEMBRANE PROTEIN CALLED CFTR:CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANE REGULATOR,WHICH IS PREDICTED TO FUNCTION AS A CAMP-REGULATED CHLORIDE CHANNEL. TO COMPLETELY CHARACTERIZE THE SPECTRUM OF MUTATIONS IN THE CFTR GENE IN GREEK CF PATIENTS, WE SCREENED 500 GREEK CF CHROMOSOMES BY DENATURING GRADIENT GEL ELECTROPHORESIS FOLLOWED BY DIRECT SEQUENCING. THE WHOLE CODINE SEQUENCING OF EXONS 1-24 AND THEIR INTRONEXONS BOUNDARIES HAVE BEEN ANALYSED .WE IDENTIFIED 54 MUTATIONS ACCOUNTING FOR 89.8% OF CF CHROMOSOMES, INCLUDING 11 NOVEL ΜUTATIONS(A46P,296+1G>C,D110E,Y247X,1497DELGG,E822X,2751+21>A,2752-26A>G,3153DELT,3272+4A>G,D1445N).ΔF508 MUTATIONS ACCOUNTS FOR 53.6% OF GREEK CF CHROMOSOMES AND ANOTHER 11 MUTATIONS HAVE FREQUENCIES >=1%, INCLUDING THE NOVEL MUTATION E822X(1.8%) SCREENING 7 EXONS OF THE CFTR GENE(10,4,11,21,13,146,176) BY DGGE, 80.4% OF CF CHROMOSOMES CAN BE DETECTED

Schizosaccharomyces pombe: a dimorphic fission yeast

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Easy, Rapid, and Cost-Effective Methods for Identifying Carriers of Recurrent GJB2 Mutations Causing Nonsyndromic Hearing Impairment in the Greek Population

A variety of techniques have been developed for screening the GJB2 gene for known and unknown mutations, especially the most common mutation in the Caucasian population, the c. 35delG. Other mutations that have been so far characterized in the GJB2 gene seem to have different geographical distributions, and therefore there is an interest in identifying recurrent mutations specific for each population and developing easy and rapid screening techniques. Here we present easy screening protocols for already identified recurrent mutations in the Greek population. Developing easy, rapid, and cost-effective screening methods will facilitate the detection of GJB2 recurrent mutation carriers, at large, in the Greek population