Marc Delpech

Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin.

We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant β(2)-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β(2)-microglobulin, the affected members of this kindred had normal renal function and normal circulating β(2)-microglobulin values. The Asp76Asn β(2)-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β(2)-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β(2)-microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.

Longest Form of CCTG Microsatellite Repeat in the Promoter of the CD2BP1/PSTPIP1 Gene Is Associated with Aseptic Abscesses and with Crohn Disease in French Patients

PurposeAseptic abscesses syndrome (AA) is an inflammatory disease in which non-infectious deep abscesses develop; these respond quickly to corticosteroids. AA is associated with Crohn disease (CD) in 57% of cases and with neutrophilic dermatosis (ND) in 20%. Pyoderma gangrenosum is usually a sporadic ND. A hereditary autosomal dominant syndromic kind of pyoderma gangrenosum, the PAPA syndrome, is linked to mutations in the CD2BP1/PSTPIP1 gene. We systematically screened this gene in French AA patients.ResultsOne microsatellite (CCTG)n with 3 alleles was identified in the promoter. The longest form (CCTG)7 was significantly more frequent in AA patients than in French controls (Pxa0=xa00.0154). We also found an association of the (CCTG)7 allele with CD in French patients (Pxa0=xa00.0351). This association was not found in a sample of Indian patients.ConclusionsThe CCTG repeat in the PSTPIP1 promoter may play a role in the pathogenesis of AA and of CD. Further investigations are required to demonstrate the possible modulation of gene expression by the (CCTG)n motif.

Next generation sequencing on patients with LGMD and nonspecific myopathies: Findings associated with ANO5 mutations

Highlights • We have carried out the largest screening of the ANO5 gene.• We identified 33 patients (4%) with pathogenic changes in both alleles and 23 heterozygotes (3%).• The identification of a ANO5 carrier is not to be considered an uncommon finding.• The anoctaminopathies have an extremely high genetic and phenotypic heterogeneity.• NGS-based strategies are perfect to dissect the clinical variability in NMDs.

Genetically determined recurrent fevers.

The usefulness of molecular diagnosis is now well established for genetically determined recurrent fevers. In familial Mediterranean fever, the severity of the disease and the risk of renal amyloidosis are correlated with mutations in MEFV, and the serum amyloid-associated protein (SAA)1 alpha/alpha allele is a modifying factor for amyloidosis. Study of the genes in various species shows that the human mutations represent a reappearance of the ancestral amino acid state and the B30-2 domain, where most human mutations are localized, is absent in the rat and mouse proteins. Since the discovery of the responsible gene, TNF-receptor-associated periodic syndrome seems to be more frequent than previously considered. Among the new mutations described, some are associated with an incomplete penetrance.

Le syndrome de fièvre héréditaire lié à un dysfonctionnement du récepteur du TNF ou Traps

PURPOSEnTumor necrosis factor receptor superfamily 1A associated periodic syndrome (TRAPS) belongs to the group of hereditary fever syndromes, also called hereditary auto-inflammatory syndromes.nnnCURRENT KNOWLEDGE AND KEY POINTSnThe diagnosis of TRAPS should be evoked in presence of the following clinical signs, whatever the population of the affected patients. TRAPS acute inflammatory access, of 1 to 3 weeks duration, is characterised by the presence of fever, abdominal pain, myalgias, various types of skin rash including erysepela-like erythema. Long term inflammatory response can lead to AA amyloidosis. Genetic testing will confirm the diagnosis when showing a mutation in the extracellular part of the TNFRSF1A receptor. Therapeutic management of TRAPS is not definitely established. Daily colchicine does not seem to prevent efficiently inflammatory attacks. Corticosteroids, in contrast can attenuate the intensity and diminish the duration of attacks.nnnFUTURE PROSPECTS AND PROJECTSnThe value of biological agents that inhibits TNF action is not yet completely determined in TRAPS. Mechanisms of the disease are not yet elucidated. In some families with specific mutations, a relative soluble TNF receptor deficiency has been found in the plasma. However this mechanism does not account for what is observed in other kindreds.Resume Propos. – Le Traps ou Tumor necrosis factor Receptor Associated Periodic fever Syndrome, que l’on peut traduire par fievre intermittente secondaire a des mutations du recepteur de type 1A du TNF (ou recepteur de 55xa0kDa) appartient au groupe des fievres hereditaires recurrentes ou syndromes auto-inflammatoires hereditaires. Actualites et points forts. – Le diagnostic de Traps doit etre evoque en presence des signes cliniques suivants et d’une histoire familiale, et cela quelle que soit la population d’origine. Les acces inflammatoires du Traps sont caracterises par leur duree de quelques jours a 3xa0semaines, la presence de douleurs abdominales, de myalgies, de lesions cutanees diverses, dont une variete de pseudoerysipele, accompagnes de fievre. L’inflammation serique est constante pendant les acces et la maladie peut se compliquer d’amylose AA. Le diagnostic de Traps repose sur l’association de signes cliniques a une mutation du recepteur de type 1A du TNF, qui peut etre cherchee a partir de l’ADN sanguin. Le traitement n’est pas bien codifie, la colchicine semble inefficace, les corticosteroides peuvent diminuer l’intensite et la duree des acces. Perspectives et projets . – La place des molecules anti-TNF dans le traitement de cette affection doit etre evaluee avec plus de recul. Les mecanismes de la maladie ne sont pas completement elucides. Il existe dans certaines familles un relatif deficit en recepteur soluble circulant, par defaut de clivage a la membrane cellulaire. Ce mecanisme ne rend pas compte de ce qui est observe pour d’autres mutations.

Fièvres intermittentes héréditaires

Resume En dehors de la fievre mediterraneenne familiale Quatre maladies hereditaires se presentant sous forme d’acces inflammatoires intermittents ont ete reconnues et maintenant bien caracterisees dans leurs aspects cliniques et genetiques. Le chef de file de ce groupe reste la fievre mediterraneenne familiale (FMF), une maladie qui affecte des milliers de personnes originaires du Bassin mediterraneen. Mais la fievre mediterraneenne familiale n’est plus seule au sein des maladies inflammatoires recurrentes hereditaires. Trois autres entites clinico-genetiques maintenant bien definies Il s’agit de la fievre intermittente secondaire a des mutations du recepteur de type 1A du Tumor Necrosis Factor (TNF), de transmission genetique autosomique dominante, le syndrome d’hyperimmunoglobulinemie D, et une derniere entite regroupant le syndrome de Muckle-Wells, l’urticaire familiale au froid et le syndrome CINCA (Chronic Infantile Neurological Cutaneous and Articular) . En pratique Un diagnostic precis de ces affections est crucial, car leur prise en charge et leur traitement sont specifiques.

Upregulation of rat P23 (a member of the YjgF protein family) by fasting, glucose diet and fatty acid feeding

Abstract.In a previous study, we identified and purified a 99-amino-acid rat liver-kidney perchloric-acid-soluble 23-kDa protein (P23) which displays 30% identity with a highly conserved domain of heat shock proteins (HSPs), as well as an AT-rich 3′ untranslated region, which has also been described to play a role in H70 mRNA life span and protein expression. An identical perchloric-acid-soluble protein inhibiting protein synthesis in a rabbit reticulocyte lysate system was also found 2xa0years later by another group. More recently, the novel, the YjgF, protein family has been described, comprising, 24 full-length homologues, including P23, highly conserved through evolution, and consisting of approximately 130 residues each and sharing a common ternary structure. Independent studies from different laboratories have provided various hypothetical functions for each of these proteins. The high degree of evolutionary conservation may suggest that these proteins play an important role in cellular regulation. Although the function of none of these proteins is known precisely, we present experimental evidence which, combined with the relationship to glucose-regulating protein revealed here, and the relationship to fatty-acid-binding protein revealed by others, allow us to propose a role for P23. In rat liver, P23 expression is developmentally regulated and modulated by dietary glucose, and its mRNA is induced by starvation, in the presence of fatty-acids and in 3-MeDAB-induced hepatomas. The mRNA encoding mouse liver P23 is also hormonally modulated in a mouse line AT1F8. These data indicate that P23 protein might be a key controller of intermediary metabolism during fasting.

A new cAMP independent protein kinase tightly bound to DNA, in rat liver nuclei.

A protein kinase has been characterized among the proteins tightly bound to DNA. It is not extracted with 1 M NaCl and is released by extensive DNase I digestion. This enzyme is able to phosphorylate nucleosomal histones, essentially H2B and H3, and several non-histone proteins associated with DNA, on serine residue(s). It does not phosphorylate protamine, casein, phosvitin and the chromosomal non-histone proteins extracted with 1 M NaCl and is cAMP independent. This protein kinase can be distinguished from the previously described enzymes.

De novo mutation in hemophilia A established by DNA haplotype analysis and precluding prenatal diagnosis

SummaryIn a family with a single case of hemophilia A genetic counselling was requested by the pregnant aunt of the propositus. The haplotypes generated by two extra-genic RFLPs, at DXS52 (St14/Taq1) and DXS15 (DX13/BglII), and one intragenic RFLP in F8C (647/BclI) indicated that: (i) she was not a carrier; (ii) the case of hemophilia resulted from a de novo mutation in a grandfathers gamete.

Breakthroughs in the genetics of hereditary fevers.

Hereditary fevers are a group of disorders characterized cavities (mainly peritoneum) joints, and skin, and the by recurrent attacks of fever and organ-localized inflammadevelopment of amyloidosis. Disease-free intervals vary tion [1]. The leader of the group remains familial Meditergreatly in length. However, subacute and chronic musculoranean fever (FMF), which is common in populations of skeletal manifestations have now been recognized. VasMediterranean ancestry. The frequency of heterozygotes in culitis affecting both small and large vessels may also be some populations affected by this recessive disease can associated with FMF. Daily colchicine treatment has a reach more than 10% [2]. The mode of genetic inheritance dramatic effect on FMF as it prevents both recurrence of makes it possible to distinguish a group of autosomal inflammatory attacks and amyloidosis. dominant recurrent fevers (ADRF) from FMF at an early After localizing the gene on the short arm of chromostage [3]. A unique biochemical abnormality has led to the some 16 (16p13.3) in 1992, two independent groups identification of the hyperimmunoglobulinemia D and simultaneously managed to actually clone the gene, MEFV, periodic fever syndrome (HIDS) in Dutch patients [4]. Our in 1997 [5,6]. MEFV encodes a protein named ‘marenosknowledge of the cause and mechanisms underlying these trin’ by the French group, referring to ‘mare nostrum’, the diseases has, until recently, been limited to few data and Latin name of the Mediterranean Sea, and called ‘pyrin’ by many speculations. During the last 3 years, however, the the American group, referring to ‘pyros’, the Greek name genes responsible for these three diseases have been for fever. The genomic sequence of MEFV predicts a basic discovered. Surprisingly, it appears that the molecular and protein of 781 amino acid residues and shares some cellular mechanisms underlying these diseases are, at least similarities with proteins of the expanding RoRet or B30.2 in part, very different. family. Indeed, this family includes several transcription factors, as well as the midin protein involved in a developmental disease, Opitz syndrome [7]. Expression of 1. Mutations in the gene encoding marenostrin /pyrin marenostrin /pyrin seems to be specific for polymorphonuprotein are responsible for familial Mediterranean clear leukocytes. Its primary structure suggests that it fever could be a neutrophil-specific transcription factor. However, marenostrin /pyrin has thus far only been localized in Familial Mediterranean fever (FMF, MIM 249100) is a the cytoplasmic compartment of the polymorphonuclear fascinating hereditary disorder affecting populations of leukocyte [8]. Mediterranean origin. The main clinical characteristics of If the physiological role of marenostrin /pyrin, as well as FMF include painful febrile attacks that last from a few the mechanisms underlying the disease, remain unknown hours to as long as 4 days and that involve the serosal to date, the discovery of MEFV led to useful diagnostic tools. About 20 mutations have now been characterized that account for about 90% of FMF alleles in populations *Corresponding author. Tel.: 133-1-4234-8084; fax: 133-1-4234at risk of the disease [9–13]. This has already led to 8588. E-mail address: gilles.grateau@htd.ap-hop-paris.fr (G. Grateau). improved clinical diagnosis and to the use of colchicine as