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Nonsyndromic hearing loss is an extremely heterogeneous disorder. Thus, clinical diagnostics is challenging, in particular due to differences in the etiology of hearing loss between populations. With this study, we wanted to elucidate the genetic basis of hearing loss in 61 consanguineous Egyptian families. In 25 families, linkage analysis was used as a prescreening to identify regions for targeted sequencing of candidate genes. Initially, the coding regions of 12 and later of 94 genes associated with hearing loss were enriched and subjected to massively parallel sequencing (MPS) with diagnostic yields of 36% and 75%, respectively. Causative variants were identified in 48 families (79%). They were found in 23 different genes with the majority being located in MYO15A (15.3%), SLC26A4 (9.7%), GJB2 (8.3%), and MYO7A (6.4%). As many as 32 variants were novel ones at the time of detection. Five variants were shared by two, three, or even four families. Our study provides a first survey of the mutational spectrum of deaf patients in Egypt revealing less GJB2 variants than in many European populations. It underlines the value of targeted enrichment of well-selected deafness genes in combination with MPS in the diagnostics of this frequent and genetically heterogeneous disorder.

The effect of addition ofvitamin E (a-tocopherol) to pig diets on muscle metabolism of phosphorus Compounds, ATPase activity and meat quality was studied. Experimental pigs were fed with a diet supplemented with vitamin E (200 mg α-tocopherol/kg diet) for 60 days before slaughtered (110 kg live weight). Longissimus muscle (LD) Vitamin E level was more than twice higher (P < 0.01) in pigs supplemented with vitamin E Changes of muscle phosphorus Compounds like sugar phosphate (SP), inorganic phosphate (Pi), phosphoereatine (PCr), and adenosinetriphosphate (ATP) assessed by 31P NMR spectroscopy (15 min post mortem) differed between control pigs and vitamin E administered pigs. Significantly lower (P < 0.05) values of SP and significantly higher values of PCr were found in pigs administered with vitamin E. Efficiency of muscle energetic metabolism measured as index PCr/Pi was higher in pigs supplemented with vitamin E. ATPase activity of longissimus muscle (LD) was not influenced by vitamin E in diet. Drip loss of LD measured 24 h post mortem and conduetivity of semimembranosus (SM) and LD measured 3 h post mortem (P < 0.05) improved by administration with vitamin E. Differences between pH of LD and SM muscles measured 45 min post mortem were not significantly influenced. Dietary vitamin E administered for 60 days to finishing pigs may have beneficial effects on muscle energetic metabolism, electrical conduetivity, and drip loss.

Mouse lines used were long-term selected for high (DU-hTP) or low treadmill Performance (DU-ITP), or high locomotor open field activity (DU-hOF). The control line DU-Ks was maintained unselected. For each line 30 mice were used at 42 days of age. All lines were split into three groups: the first group was investigated without running exercise, the second had to run 500 m, and the third had to run until exhaustion on the treadmill. Compared to mice without running, in exhausted mice the maximal rate of SR Ca2+ uptake of the m. rectus femoris decreases were only found in the mouse lines DU-ITP, and DU-hOF (28.5 %, and 36.3 %, respectively; p < 0.05). The effect of the 500 m run was significant (p < 0.05) in DU-hTP, but not in the other lines. An effect of exhausting exercise on Ca2* ATPase was detected only in DU-hOF with increased values after the exhaustive run. The hypothesis, that exercise induced alterations in Ca2* transport in muscle of mice selected for high activity (DU-hOF) or high running Performance (DU-hTP) are attenuated compared to mice which were not selected (DU-Ks) or selected for low Performance (DU-ITP), could not be verified.

Ubiquitination plays a crucial role in neurodevelopment as exemplified by Angelman syndrome, which is caused by genetic alterations of the ubiquitin ligase-encoding UBE3A gene. Although the function of UBE3A has been widely studied, little is known about its paralog UBE3B. By using exome and capillary sequencing, we here identify biallelic UBE3B mutations in four patients from three unrelated families presenting an autosomal-recessive blepharophimosis- ptosis-intellectual-disability syndrome characterized by developmental delay, growth retardation with a small head circumference, facial dysmorphisms, and low cholesterol levels. UBE3B encodes an uncharacterized E3 ubiquitin ligase. The identified UBE3B variants include one frameshift and two splice-site mutations as well as a missense substitution affecting the highly conserved HECT domain. Disruption of mouse Ube3b leads to reduced viability and recapitulates key aspects of the human disorder, such as reduced weight and brain size and a downregulation of cholesterol synthesis. We establish that the probable Caenorhabditis elegans ortholog of UBE3B, oxi-1, functions in the ubiquitin/proteasome system in vivo and is especially required under oxidative stress conditions. Our data reveal the pleiotropic effects of UBE3B deficiency and reinforce the physiological importance of ubiquitination in neuronal development and function in mammals. © 2012 The American Society of Human Genetics., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Frank-ter Haar syndrome is a rare disorder associated with skeletal, cardiac, ocular and craniofacial features including hypertelorism and brachycephaly. The most common underlying genetic defect in Frank-ter Haar syndrome appears to be a mutation in the SH3PXD2B gene on chromosome 5q35.1. Craniosynostosis, or premature fusion of the calvarial sutures, has not previously been described in Frank-ter Haar syndrome. Case presentation We present a family of three affected siblings born to consanguineous parents with clinical features in keeping with a diagnosis of Frank-ter Haar syndrome. All three siblings have a novel mutation caused by the deletion of exon 13 of the SH3PXD2B gene. Two of the three siblings also have non-scaphocephalic sagittal synostosis associated with raised intracranial pressure. Conclusion The clinical features of craniosynostosis and raised intracranial pressure in this family with a confirmed diagnosis of Frank-ter Haar syndrome expand the clinical spectrum of the disease. The abnormal cranial proportions in a mouse model of the disease suggests that the association is not coincidental. The possibility of craniosynostosis should be considered in individuals with a suspected diagnosis of Frank-ter Haar syndrome.

Contains fulltext : 69886.pdf (Publisher’s version ) (Open Access) PURPOSE: The goal of this study was to identify mutations in X-chromosomal genes associated with retinitis pigmentosa (RP) in patients from Germany, The Netherlands, Denmark, and Switzerland. METHODS: In addition to all coding exons of RP2, exons 1 through 15, 9a, ORF15, 15a and 15b of RPGR were screened for mutations. PCR products were amplified from genomic DNA extracted from blood samples and analyzed by direct sequencing. In one family with apparently dominant inheritance of RP, linkage analysis identified an interval on the X chromosome containing RPGR, and mutation screening revealed a pathogenic variant in this gene. Patients of this family were examined clinically and by X-inactivation studies. RESULTS: This study included 141 RP families with possible X-chromosomal inheritance. In total, we identified 46 families with pathogenic sequence alterations in RPGR and RP2, of which 17 mutations have not been described previously. Two of the novel mutations represent the most 3'-terminal pathogenic sequence variants in RPGR and RP2 reported to date. In exon ORF15 of RPGR, we found eight novel and 14 known mutations. All lead to a disruption of open reading frame. Of the families with suggested X-chromosomal inheritance, 35% showed mutations in ORF15. In addition, we found five novel mutations in other exons of RPGR and four in RP2. Deletions in ORF15 of RPGR were identified in three families in which female carriers showed variable manifestation of the phenotype. Furthermore, an ORF15 mutation was found in an RP patient who additionally carries a 6.4 kbp deletion downstream of the coding region of exon ORF15. We did not identify mutations in 39 sporadic male cases from Switzerland. CONCLUSIONS: RPGR mutations were confirmed to be the most frequent cause of RP in families with an X-chromosomal inheritance pattern. We propose a screening strategy to provide molecular diagnostics in these families.