Gérard Lefranc

Calpain 3 deficiency is associated with myonuclear apoptosis and profoundperturbation of the IκBα/NF-κB pathway in limb-girdle musculardystrophy type 2A

Nature Med. 5, 503– 511 (1999). The top left corner of Fig. 1b on page 505 was cropped so that you could not view the calpain 3-stained nuclei in endomysia space. The corrected figure is shown below. We regret this error.

Deep Dermatophytosis and Inherited CARD9 Deficiency

BACKGROUND Deep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause. METHODS We studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients. RESULTS Four patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance. CONCLUSIONS All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.).

Evidence for balancing selection from nucleotide sequence analyses of human G6PD.

Glucose-6-phosphate dehydrogenase (G6PD) mutations that result in reduced enzyme activity have been implicated in malarial resistance and constitute one of the best examples of selection in the human genome. In the present study, we characterize the nucleotide diversity across a 5.2-kb region of G6PD in a sample of 160 Africans and 56 non-Africans, to determine how selection has shaped patterns of DNA variation at this gene. Our global sample of enzymatically normal B alleles and A, A-, and Med alleles with reduced enzyme activities reveals many previously uncharacterized silent-site polymorphisms. In comparison with the absence of amino acid divergence between human and chimpanzee G6PD sequences, we find that the number of G6PD amino acid polymorphisms in human populations is significantly high. Unlike many other G6PD-activity alleles with reduced activity, we find that the age of the A variant, which is common in Africa, may not be consistent with the recent emergence of severe malaria and therefore may have originally had a historically different adaptive function. Overall, our observations strongly support previous genotype-phenotype association studies that proposed that balancing selection maintains G6PD deficiencies within human populations. The present study demonstrates that nucleotide sequence analyses can reveal signatures of both historical and recent selection in the genome and may elucidate the impact that infectious disease has had during human evolution.

DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation

The adaptors DOCK8 and MyD88 have been linked to serological memory. Here we report that DOCK8-deficient patients had impaired antibody responses and considerably fewer CD27+ memory B cells. B cell proliferation and immunoglobulin production driven by Toll-like receptor 9 (TLR9) were considerably lower in DOCK8-deficient B cells, but those driven by the costimulatory molecule CD40 were not. In contrast, TLR9-driven expression of AICDA (which encodes the cytidine deaminase AID), the immunoglobulin receptor CD23 and the costimulatory molecule CD86 and activation of the transcription factor NF-κB, the kinase p38 and the GTPase Rac1 were intact. DOCK8 associated constitutively with MyD88 and the tyrosine kinase Pyk2 in normal B cells. After ligation of TLR9, DOCK8 became tyrosine-phosphorylated by Pyk2, bound the Src-family kinase Lyn and linked TLR9 to a Src–kinase Syk–transcription factor STAT3 cascade essential for TLR9-driven B cell proliferation and differentiation. Thus, DOCK8 functions as an adaptor in a TLR9-MyD88 signaling pathway in B cells.

Alu insertion polymorphisms in NW Africa and the Iberian Peninsula: evidence for a strong genetic boundary through the Gibraltar Straits

Abstract. An analysis of 11 Alu insertion polymorphisms (ACE, TPA25, PV92, APO, FXIIIB, D1, A25, B65, HS2.43, HS3.23, and HS4.65) has been performed in several NW African (Northern, Western, and Southeastern Moroccans; Saharawi; Algerians; Tunisians) and Iberian (Basques, Catalans, and Andalusians) populations. Genetic distances and principal component analyses show a clear differentiation of NW African and Iberian groups of samples, suggesting a strong genetic barrier matching the geographical Mediterranean Sea barrier. The restriction to gene flow may be attributed to the navigational hazards across the Straits, but cultural factors must also have played a role. Some degree of gene flow from sub-Saharan Africa can be detected in the southern part of North Africa and in Saharawi and Southeastern Moroccans, as a result of a continuous gene flow across the Sahara desert that has created a south-north cline of sub-Saharan Africa influence in North Africa. Iberian samples show a substantial degree of homogeneity and fall within the cluster of European-based genetic diversity.

Update in chronic obstructive pulmonary disease: role of antioxidant and metabolizing gene polymorphisms

ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by systemic and local chronic inflammation and oxidative stress. The sources of the increased oxidative stress in COPD patients derive from the increased burden of inhaled oxidants such as cigarette smoke and other forms of particulate or gaseous air pollution and from the increase in reactive oxygen species (ROS) generated by several inflammatory, immune, and structural airways cells. There is increasing evidence that genetic factors may also contribute to the pathogenesis if COPD, particularly antioxidant genes, which may confer a susceptibility to environmental insults such as cigarette smoke and thereafter development of COPD. Consequently, heme oxygenase-1 (HO-1), superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), microsomal epoxide hydrolase (EPHX1), and cytochrome P450 (CYP) genetic polymorphisms may have an important role in COPD pathogenesis. In this review the authors summarized the most recent findings dealing with these antioxidant genes contributing to the free radical neutralization and xenobiotic enzymes playing a role in different phases of cell detoxification reactions related to the redox status imbalance in COPD, with an emphasis on their possible roles in disease progression.

Joining the pillars of Hercules: mtDNA sequences show multidirectional gene flow in the western Mediterranean.

Phylogenetic analysis of mitochondrial DNA (mtDNA) performed in Western Mediterranean populations has shown that both shores share a common set of mtDNA haplogroups already found in Europe and the Middle East. Principal co‐ordinates of genetic distances and principal components analyses based on the haplotype frequencies show that the main genetic difference is attributed to the higher frequency of sub‐Saharan L haplogroups in NW Africa, showing some gene flow across the Sahara desert, with a major impact in the southern populations of NW Africa. The AMOVA demonstrates that SW European populations are highly homogeneous whereas NW African populations display a more heterogeneous genetic pattern, due to an east‐west differentiation as a result of gene flow coming from the East. Despite the shared haplogroups found in both areas, the European V and the NW African U6 haplogroups reveal the traces of the Mediterranean Sea permeability to female migrations, and allowed for determination and quantification of the genetic contribution of both shores to the genetic landscape of the geographic area.

IMGT®, the international ImMunoGeneTics information system® 25 years on

IMGT®, the international ImMunoGeneTics information system®(http://www.imgt.org) is the global reference in immunogenetics and immunoinformatics. By its creation in 1989 by Marie-Paule Lefranc (Université de Montpellier and CNRS), IMGT® marked the advent of immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics. IMGT® is specialized in the immunoglobulins (IG) or antibodies, T cell receptors (TR), major histocompatibility (MH) and proteins of the IgSF and MhSF superfamilies. IMGT® is built on the IMGT-ONTOLOGY axioms and concepts, which bridged the gap between genes, sequences and 3D structures. The concepts include the IMGT® standardized keywords (identification), IMGT® standardized labels (description), IMGT® standardized nomenclature (classification), IMGT unique numbering and IMGT Colliers de Perles (numerotation). IMGT® comprises 7 databases, 17 online tools and 15 000 pages of web resources, and provides a high-quality and integrated system for analysis of the genomic and expressed IG and TR repertoire of the adaptive immune responses, including NGS high-throughput data. Tools and databases are used in basic, veterinary and medical research, in clinical applications (mutation analysis in leukemia and lymphoma) and in antibody engineering and humanization. The IMGT/mAb-DB interface was developed for therapeutic antibodies and fusion proteins for immunological applications (FPIA). IMGT® is freely available at http://www.imgt.org.

Mutations in OSTM1 (Grey Lethal) Define a Particularly Severe Form of Autosomal Recessive Osteopetrosis With Neural Involvement

We report three novel osteopetrosis patients with OSTM1 mutations and review two that have been previously described. Our analysis suggests that OSTM1 defines a new subset of patients with severe central nervous system involvement. This defect is also present in the gl mouse, which could represent a good model to study the role of the gene in the pathogenesis of this disease.

Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups

We performed clinical, immunological and genetic studies of 12 hyper-IgE syndrome (HIES) patients from 4 Hungarian, 2 Lebanese, one Russian, one Polish, and one Swedish families with autosomal dominant (AD) or sporadic forms of the disease to reveal cross-ethnicity of recurrent and novel mutations in the signal transducer and activator of transcription-3 gene (STAT3). Four patients from 3 Hungarian families, and one Russian, and one Swedish patient carried the heterozygous R382W germline mutation at the DNA-binding site of STAT3. The recurrent V637M mutation affecting the SRC homology 2 (SH2) domain was detected in one Lebanese and one Polish family, and the V463del deletion located in the DNA-binding domain was unveiled in another Lebanese family. A novel H332Y mutation affecting the DNA-binding site of STAT3 in three Hungarian patients from a Gypsy family was also found. The segregation of this mutation with HIES, restriction fragment length polymorphism analysis of STAT3 from patients and controls and the negligible production upon IL-6 stimulation of monocyte chemotactic protein-1 by the patients blood mononuclear cells suggested that the H332Y mutation was disease-causing. These data suggest, that dominant negative mutations of the DNA-binding and SH2 domains of STAT3 cause AD and sporadic cases of HIES in different ethnic groups with R382W as the predominant mutation found in 5 of the 9 families. Functional and genetic data support that the novel H332Y mutation may result in the loss of function of STAT3 and leads to the HIES phenotype.