Branched-chain amino acid database integrated in MEDIPAD software as a tool for nutritional investigation of mediterranean populations

Branched-chained amino acids (BCAA) are essential dietary components for humans and can act as potential biomarkers for diabetes development. To efficiently estimate dietary intake, we developed a BCAA database for 1331 food items found in the French Centre d'Information sur la Qualité des Aliments (CIQUAL) food table by compiling BCAA content from international tables, published measurements, or by food similarity as well as by calculating 267 items from Greek, Turkish, Romanian, and Moroccan mixed dishes. The database embedded in MEDIPAD software capable of registering 24 h of dietary recalls (24HDR) with clinical and genetic data was evaluated based on archived 24HDR of the Saint Pierre Institute (France) from 2957 subjects, which indicated a BCAA content up to 4.2 g/100 g of food and differences among normal weight and obese subjects across BCAA quartiles. We also evaluated the database of 119 interviews of Romanians, Turkish and Albanians in Greece (27⁻65 years) during the MEDIGENE program, which indicated mean BCAA intake of 13.84 and 12.91 g/day in males and females, respectively, comparable to other studies. The MEDIPAD is user-friendly, multilingual, and secure software and with the BCAA database is suitable for conducting nutritional assessment in the Mediterranean area with particular facilities for food administration

Prévalence de la population de poids normal, métaboliquement obèse, chez l'adolescent [Prevalence of metabolically obese normal weight population in adolescent]

Introduction. Several studies have shown that a subgroup of individuals with normal weight have metabolic characteristics usually associated with obesity and would be also at increased risk of cardiovascular complications, as well as the obese individual. This syndrome is described as metabolically normal-weight obese (MONW) syndrome. Objective. To evaluate the prevalence of MONW topics in a young population aged 16- 19 years. Population and Methods. Nine hundred adolescents (565 girls/335 boys), aged 16-19 years without history of diabetes or high blood pressure, enrolled in two schools of Bir Khadem city, were detected after informed parental consent. Anthropometric measurements (weight, height, waist circumference (WC), hip circumference (HC), and blood pressure were evaluated. Fasting blood glucose and triglyceride levels were determined. Criteria and Ruderman score were used to define MONW topics. Results. 37 patients (30 girls and 7 boys) were MONW with a score ≥ 7. In these subjects, diabetes history seemed to be the predominant criteria for boys, and high waistline predominated in girls. Conclusion. MONW syndrome differs from the metabolic syndrome by the BMI criteria which is normal here. Concerning the pathophysiology and associated complications, they remain the same in the both cases

EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness.

International audienceBACKGROUND: Almost 90% of all cases of congenital, non-syndromic, severe to profound inherited deafness display an autosomal recessive mode of transmission (DFNB forms). To date, 47 causal DFNB genes have been identified, but many others remain to be discovered. We report the study of two siblings born to consanguineous Algerian parents and affected by isolated, profound congenital deafness. METHOD: Whole-exome sequencing was carried out on these patients after a failure to identify mutations in the DFNB genes frequently involved. RESULTS: A biallelic nonsense mutation, c.88C > T (p.Gln30*), was identified in EPS8 that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics. This mutation predicts a truncated inactive protein or no protein at all. The mutation was also present, in the heterozygous state, in one clinically unaffected sibling and in both unaffected parents, and was absent from the other two unaffected siblings. It was not found in 120 Algerian normal hearing control individuals or in the Exome Variant Server database. EPS8 is an F-actin capping and bundling protein. Mutant mice lacking EPS8 (Eps8-/- mice), which is present in the hair bundle, the sensory antenna of the auditory sensory cells that operate the mechano-electrical transduction, are also profoundly deaf and have abnormally short hair bundle stereocilia. CONCLUSION: This new DFNB form is likely to arise from abnormal hair bundles resulting in compromised detection of physiological sound pressures

Diversity of the Genes Implicated in Algerian Patients Affected by Usher Syndrome.

Usher syndrome (USH) is an autosomal recessive disorder characterized by a dual sensory impairment affecting hearing and vision. USH is clinically and genetically heterogeneous. Ten different causal genes have been reported. We studied the molecular bases of the disease in 18 unrelated Algerian patients by targeted-exome sequencing, and identified the causal biallelic mutations in all of them: 16 patients carried the mutations at the homozygous state and 2 at the compound heterozygous state. Nine of the 17 different mutations detected in MYO7A (1 of 5 mutations), CDH23 (4 of 7 mutations), PCDH15 (1 mutation), USH1C (1 mutation), USH1G (1 mutation), and USH2A (1 of 2 mutations), had not been previously reported. The deleterious consequences of a missense mutation of CDH23 (p.Asp1501Asn) and the in-frame single codon deletion in USH1G (p.Ala397del) on the corresponding proteins were predicted from the solved 3D-structures of extracellular cadherin (EC) domains of cadherin-23 and the sterile alpha motif (SAM) domain of USH1G/sans, respectively. In addition, we were able to show that the USH1G mutation is likely to affect the binding interface between the SAM domain and USH1C/harmonin. This should spur the use of 3D-structures, not only of isolated protein domains, but also of protein-protein interaction interfaces, to predict the functional impact of mutations detected in the USH genes

The CD2 isoform of protocadherin-15 is an essential component of the tip-link complex in mature auditory hair cells

International audienceProtocadherin-15 (Pcdh15) is a component of the tip-links, the extracellular filaments that gate hair cell mechano-electrical transduction channels in the inner ear. There are three Pcdh15 splice isoforms (CD1, CD2 and CD3), which only differ by their cyto-plasmic domains; they are thought to function redundantly in mechano-electrical transduction during hair-bundle development, but whether any of these isoforms composes the tip-link in mature hair cells remains unknown. By immunolabelling and both morphological and electrophysiological analyses of post-natal hair cell-specific conditional knockout mice (Pcdh15 ex38-fl/ex38-fl Myo15-cre +/À) that lose only this isoform after normal hair-bundle development, we show that Pcdh15-CD2 is an essential component of tip-links in mature auditory hair cells. The finding, in the homozygous or compound heterozygous state, of a PCDH15 frameshift mutation (p.P1515Tfs*4) that affects only Pcdh15-CD2, in profoundly deaf children from two unrelated families, extends this conclusion to humans. These results provide key information for identification of new components of the mature auditory mechano-electrical trans-duction machinery. This will also serve as a basis for the development of gene therapy for deafness caused by PCDH15 defects

Predicted pathogenicity of the six missense mutations found in Algerian USH patients.

<p>Predicted pathogenicity of the six missense mutations found in Algerian USH patients.</p

Predicted effect of the p.Ala397del <i>USH1G</i> mutation.

<p>(A) On the left side, ribbon diagram showing the hydrophobic core of the SAM domain of USH1G/sans. The side chains of the hydrophobic residues Leu392, Phe395, Leu396, and Leu399 and of the polar residue His400 of the αA helix are represented in green and in blue, respectively. On the right side, the ribbon diagram shows the disruption of the hydrophobic core of the SAM domain by the His400 polar residue in the presence of the p.Ala397del mutation. (B) On the left side, ribbon diagram showing the overall structure of the Nter-PDZ1 domain of USH1C/harmonin (cyan) interacting with the SAM domain of USH1G/sans (orange). The αA helix of the SAM domain interacts with the surface groove of the harmonin PDZ1 domain. Note the major involvement of the SAM domain residues Thr394, Ala397, and His400 in this interaction. On the right side, the ribbon diagram shows the abnormal SAM-PDZ1 interaction interface in the presence of the p.Ala397del mutation: the Leu151 and Thr156 residues of the PDZ1 domain cannot interact with the missing Ala397 residue and the His400 residue of the SAM domain, respectively.</p

Schematic representation of myosin-VIIa (USH1B), harmonin (USH1C), cadherin-23 (USH1D), protocadherin-15 (USH1F), sans (USH1G), and usherin (USH2A).

<p>For each protein, the longest isoform is shown. The novel and the previously reported causal mutations in Algerian USH patients are indicated in red and in black, respectively. Abbreviations: <i>IQ</i>, isoleucine-glutamine motifs; <i>MyTH4</i>, myosin tail homology 4 domain; <i>FERM</i>, band 4.1-ezrin-radixin-moesin domain; <i>SH3</i>, src homology 3 domain; <i>Nter</i>, N-terminal domain; <i>PDZ</i>, PSD95-discs large-ZO1 domain; <i>CC</i>, coiled coil domain; <i>PST</i>, proline-serine-threonine-rich region; <i>EC</i>, extracellular cadherin domain; <i>TM</i>, transmembrane domain; <i>Ank</i>, ankyrin domain; <i>SAM</i>, sterile alpha motif domain; <i>LamG/TspN/PTX</i>, N-terminal thrombospondin/pentaxin/laminin G-like domain; <i>Lam Nter</i>, laminin N-terminal domain; <i>Lam EGF-like</i>, laminin-type EGF-like domain; <i>Lam G-like</i>, laminin G-like domain; <i>FNIII</i>, fibronectin type III domain.</p