Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects

BACKGROUND: Familial mediterranean fever (FMF) is a recessively inherited disease characterized by recurrent crises of fever, abdominal, articular and/or thoracic pain. The most severe complication is the development of renal amyloidosis. Over 35 mutations have been discovered so far in the gene responsible for the disease, MEFV. This article aims at determining a correlation between the MEFV genotype and the occurence of amyloidosis in FMF patients, in addition to the study of the modifying effects of the SAA1 (type 1 serum amyloid A protein) and MICA (Major Histocompatibility Complex (MHC) class-I-chain-related gene A) genes on this severe complication. METHODS: Fourteen MEFV mutations were screened and the SAA1 and MICA polymorphisms tested in 30 FMF patients with amyloidosis and 40 FMF patients without amyloidosis. RESULTS: The M694V and V726A allelic frequencies were, respectively, significantly higher and lower in the group with amyloidosis, compared to the control FMF group. The beta and gamma SAA1 alleles were more frequently encountered in the group without amyloidosis, whereas the alpha allele was significantly more observed in FMF patients with amyloidosis (p < 0.025). All the MICA alleles were encountered in both patients' groups, but none of them was significantly associated with amyloidosis. CONCLUSIONS: The results suggest a protective effect of the SAA1 beta and gamma alleles on the development of amyloidosis and show the absence of a MICA modifying effect on amyloidosis development. Testing these polymorphisms on a larger sample will lead to more definite conclusions

A severe clinical phenotype of Noonan syndrome with neonatal hypertrophic cardiomyopathy in the second case worldwide with RAF1 S259Y neomutation

International audienceNoonan syndrome and related disorders are a group of clinically and genetically heterogeneous conditions caused by mutations in genes of the RAS/MAPK pathway. Noonan syndrome causes multiple congenital anomalies, which are frequently accompanied by hypertrophic cardiomyopathy (HCM). We report here a Tunisian patient with a severe phenotype of Noonan syndrome including neonatal HCM, facial dysmorphism, severe failure to thrive, cutaneous abnormalities, pectus excavatum and severe stunted growth, who died in her eighth month of life. Using whole exome sequencing, we identified a de novo mutation in exon 7 of the RAF1 gene: c.776C > A (p.Ser259Tyr). This mutation affects a highly conserved serine residue, a main mediator of Raf-1 inhibition via phosphorylation. To our knowledge the c.776C > A mutation has been previously reported in only one case with prenatally diagnosed Noonan syndrome. Our study further supports the striking correlation of RAF1 mutations with HCM and highlights the clinical severity of Noonan syndrome associated with a RAF1 p.Ser259Tyr mutation

FANCA Gene Mutations in North African Fanconi Anemia Patients

Populations in North Africa (NA) are characterized by a high rate of consanguinity. Consequently, the proportion of founder mutations might be higher than expected and could be a major cause for the high prevalence of recessive genetic disorders like Fanconi anemia (FA). We report clinical, cytogenetic, and molecular characterization of FANCA in 29 North African FA patients from Tunisia, Libya, and Algeria. Cytogenetic tests revealed high rates of spontaneous chromosome breakages for all patients except two of them. FANCA molecular analysis was performed using three different molecular approaches which allowed us to identify causal mutations as homozygous or compound heterozygous forms. It included a nonsense mutation (c.2749C > T; p.Arg917Ter), one reported missense mutation (c.1304G > A; p.Arg435His), a novel missense variant (c.1258G > A; p.Asp409Glu), and the FANCA most common reported mutation (c.3788_3790delTCT; p.Phe1263del). Furthermore, three founder mutations were identified in 86.7% of the 22 Tunisian patients: (1) a deletion of exon 15, in 36.4% patients (8/22); (2), a deletion of exons 4 and 5 in 23% (5/22) and (3) an intronic mutation c.2222 + 166G > A, in 27.3% (6/22). Despite the relatively small number of patients studied, our results depict the mutational landscape of FA among NA populations and it should be taken into consideration for appropriate genetic counseling

Contribution à l'étude des maladies neurologiques au Liban (localisation et identification de gènes)

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Identification de gènes et caractérisation des altérations moléculaires impliquées dans les neuropathies héréditaires à transmission autosomique récessive dans un panel de familles consanguines

Ce travail de thèse s'est axé sur l'identification de nouveaux loci impliqués dans les neuropathies héréditaires à transmission autosomique récessive et la caractérisation des gènes impliqués dans ces défauts moléculaires. L'utilisation de la stratégie classique de cartographie par homozygotie, alliée à une panoplie d'outils moléculaires, nous a permis d'explorer un panel de familles consanguines, notamment Algériennes et Libanaises, puis ensuite de caractériser pour certaines d'entre elles l'altération moléculaire précise en cause dans le phénotype observé, et l'identification d'un nouveau loci dont le gène a pu être caractérisé. L'étude plus particulière de familles CMT2B1 a permis d'estimer par datation l'âge d'une mutation récurrente unique à effet fondateur en Algérie. L'analyse de familles consanguines présentant un phénotype CCFDN typique ou partiel ont été explorées pour caractériser l'altération génétique responsable de la maladie et essayer d'apprécier la variabilité phénotypique observée.This thesis focused on the identification of new loci involved in autosomal recessive hereditary neuropathies and the characterization of the causative genes and molecular defects. The use of the classical strategy of homozygosity mapping, as well as a set of molecular tools, allowed us to explore a panel of consanguineous families, notably Algerian and Lebanese families, and to characterize for some of them the fine molecular defect responsible of the observed phenotype, and the identification of a new locus whose gene has been futher characterized. Particularly, the study of CMT2B1 families allowed us to estimate the age of a unique recurrent mutation with founder effect in Algeria. Analysis of consanguineous families showing typical or partial CCFDN phenotype have been explored to characterize the genetic defect responsible of the disease and to try to explain partially the phenotypic variability observed.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Identification du gène responsable du syndrome CAMOS, une forme autosomique récessive d'ataxie cérébelleuse congénitale non progressive

CAMOS (Cerebellar Ataxia with Mental retardation, Optic atrophy and Skin abnormalities) est une ataxie cérébelleuse non-progressive à transmission autosomique récessive associée à un retard mental, une atrophie optique et des anomalies ultrastructurales de la peau. Une étude de liaison génétique réalisée sur une famille libanaise consanguine a permis de localiser le gène causatif en 15q24-q26. Par une approche de gènes candidats, nous avons identifié une mutation faux-sens c.3136G>A (p.Gly1046Arg) dans ZNF592, gène codant une protéine à doigt de zinc. L'étude transcriptionnelle a exclu la présence d'anomalies d'épissage. Des analyses d'expression ont montré que ZNF592 a une expression ubiquitaire avec une forte expression dans le muscle. La localisation de la mutation dans un domaine C2H2 fonctionnel, l'analyse in silico prédisant le remplacement de deux domaines C2H2 par un domaine FYVE et la création d'un pont d'hydrogène dans le domaine muté sont en forte faveur de l'effet pathogénique de la mutation. L'identification de ZNF592 aidera à la compréhension de la physiopathologie de cette maladie.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Reply: Autosomal recessive cerebellar ataxia caused by a homozygous mutation in PMPCA

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51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), Milan, ITALY, JUN 16-19, 2018International audienc