A Guillain-Barré syndrome-associated SIGLEC10 rare variant impairs its recognition of gangliosides.

Guillain-Barré syndrome (GBS), including its variant Miller Fisher syndrome (MFS), is an acute peripheral neuropathy that involves autoimmune mechanisms leading to the production of autoantibodies to gangliosides; sialic acid-containing glycosphingolipids. Although association with various genetic polymorphisms in the major histocompatibility complex (MHC) is shown in other autoimmune diseases, GBS is an exception, showing no such link. No significant association was found by genome wide association studies, suggesting that GBS is not associated with common variants. To address the involvement of rare variants in GBS, we analyzed Siglec-10, a sialic acid-recognizing inhibitory receptor expressed on B cells. Here we demonstrate that two rare variants encoding R47Q and A108V substitutions in the ligand-binding domain are significantly accumulated in patients with GBS. Because of strong linkage disequilibrium, there was no patient carrying only one of them. Recombinant Siglec-10 protein containing R47Q but not A108V shows impaired binding to gangliosides. Homology modeling revealed that the R47Q substitution causes marked alteration in the ligand-binding site. Thus, GBS is associated with a rare variant of the SIGLEC10 gene that impairs ligand binding of Siglec-10. Because Siglec-10 regulates antibody production to sialylated antigens, our finding suggests that Siglec-10 regulates development of GBS by suppressing antibody production to gangliosides, with defects in its function predisposing to disease.

Familial Miller Fisher syndrome.

Miller Fisher syndrome is an acute inflammatory polyradiculoneuropathy that is generally considered a variant of Guillain-Barré syndrome and is characterized by the clinical triad of ataxia, areflexia, and ophthalmoplegia. Several reports of familial Guillain-Barré syndrome have been reported, indicating a possible underlying genetic and/or environmental predisposition to the development of Guillain-Barré syndrome. A familial association in Miller Fisher syndrome has not previously been described in the literature. We report 2 cases of Miller Fisher syndrome presenting simultaneously in siblings, with a review of recent relevant literature.

Comparative genomic analysis of Campylobacter jejuni associated with Guillain-Barré and Miller Fisher syndromes: neuropathogenic and enteritis-associated isolates can share high levels of genomic similarity.

BACKGROUND: Campylobacter jejuni infection represents the most frequent antecedent infection triggering the onset of the neuropathic disorders Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS). Although sialylated ganglioside-mimicking lipo-oligosaccharide (LOS) structures are the strongest neuropathogenic determinants in C. jejuni, they do not appear to be the only requirement for a neuropathic outcome since strains capable of their production have been isolated from patients with uncomplicated cases of enteritis. Consequently, other pathogen and/or host-related factors contribute to the onset of neurological complications. We have used comparative genomic hybridization to perform a detailed genomic comparison of strains isolated from GBS/MFS and enteritis-only patients. Our dataset, in which the gene conservation profile for 1712 genes was assayed in 102 strains, including 56 neuropathogenic isolates, represents the largest systematic search for C. jejuni factors associated with GBS/MFS to date and has allowed us to analyze the genetic background of neuropathogenic C. jejuni strains with an unprecedented level of resolution. RESULTS: The majority of GBS/MFS strains can be assigned to one of six major lineages, suggesting that several genetic backgrounds can result in a neuropathogenic phenotype. A statistical analysis of gene conservation rates revealed that although genes involved in the sialylation of LOS structures were significantly associated with neuropathogenic strains, still many enteritis-control strains both bear these genes and share remarkable levels of genomic similarity with their neuropathogenic counterparts. Two capsule biosynthesis genes (Cj1421c and Cj1428c) showed higher conservation rates among neuropathogenic strains compared to enteritis-control strains. Any potential involvement of these genes in neuropathogenesis must be assessed. A single gene (HS:3 Cj1135) had a higher conservation rate among enteritis-control strains. This gene encodes a glucosyltransferase that is found in some of the LOS classes that do not express ganglioside mimics. CONCLUSION: Our findings corroborate that neuropathogenic factors may be transferred between unrelated strains of different genetic background. Our results would also suggest that the failure of some strains isolated from uncomplicated cases of enteritis to elicit a neuropathic clinical outcome may be due to subtle genetic differences that silence their neuropathogenic potential and/or due to host-related factors.

Commonality and biosynthesis of the O-methyl phosphoramidate capsule modification in Campylobacter jejuni.

In this study we investigated the commonality and biosynthesis of the O-methyl phosphoramidate (MeOPN) group found on the capsular polysaccharide (CPS) of Campylobacter jejuni. High resolution magic angle spinning NMR spectroscopy was used as a rapid, high throughput means to examine multiple isolates, analyze the cecal contents of colonized chickens, and screen a library of CPS mutants for the presence of MeOPN. Sixty eight percent of C. jejuni strains were found to express the MeOPN with a high prevalence among isolates from enteritis, Guillain Barré, and Miller-Fisher syndrome patients. In contrast, MeOPN was not observed for any of the Campylobacter coli strains examined. The MeOPN was detected on C. jejuni retrieved from cecal contents of colonized chickens demonstrating that the modification is expressed by bacteria inhabiting the avian gastrointestinal tract. In C. jejuni 11168H, the cj1415-cj1418 cluster was shown to be involved in the biosynthesis of MeOPN. Genetic complementation studies and NMR/mass spectrometric analyses of CPS from this strain also revealed that cj1421 and cj1422 encode MeOPN transferases. Cj1421 adds the MeOPN to C-3 of the beta-d-GalfNAc residue, whereas Cj1422 transfers the MeOPN to C-4 of D-glycero-alpha-L-gluco-heptopyranose. CPS produced by the 11168H strain was found to be extensively modified with variable MeOPN, methyl, ethanolamine, and N-glycerol groups. These findings establish the importance of the MeOPN as a diagnostic marker and therapeutic target for C. jejuni and set the groundwork for future studies aimed at the detailed elucidation of the MeOPN biosynthetic pathway.

Actualización en Citogenética molecular / Molecular cytogenetics: an updat

La citogenética molecular es una poderosa herramienta en el diagnóstico e investigaciones actuales, donde la hibridación in situ con fluorescencia (FISH) es uno de sus puntales. De acuerdo al diagnóstico o investigación a realizar se selecciona el tipo de sonda a utilizar; así, tenemos que las sondas genes-específicas son útiles en la detecciónde enfermedades en las que se conoce la secuencia génica afectada; las sondas de secuencias repetitivas son utilizadas en la detección de aneuploidías y estudios de retraso mental. Otra variante como el CGH (Comparative Genomic Hybridisation), es una nueva tecnología donde se compara el ADN tumoral y ADN normal, marcados con fluorocromos diferentes, permitiendo detectar ganancias o pérdidas en el ADN del tumor y hacer predicciones de su evolución y posible tratamiento. Por otro lado, el SKY permite detectar translocaciones crípticas al colorear cada cromosoma con un color diferente y el Rx-FISH nos permite detectar aberraciones intracromosómicas, además de identificar anillos y cromosomas marcadores...(AU)

[Miller-Fisher syndrome]. / Miller-Fishers syndrom.

BACKGROUND: Miller-Fisher syndrome is characterised by the clinical triad of ophthalmoplegia, ataxia and areflexia and is considered a variant form of Guillain-Barré syndrome. In western countries the incidence is reported to be approximately 1-5% that of Guillain-Barré syndrome. Approximately 90% of patients have antibodies against the ganglioside GQ1b, which is of diagnostic and pathogenic importance. MATERIAL AND METHODS: We present two patients with Miller-Fisher syndrome and describe clinical features and possible mechanisms of GQ1b antibodies. RESULTS AND INTERPRETATION: Both patients presented with the classical triad of symptoms and GQ1b antibodies after upper respiratory tract infections. One of the patients had a more severe form with additional bulbar signs and was treated with plasma exchange. Both made almost complete recoveries within a few months.

[The association between HLA typing and different subtypes of Guillain Barré syndrome].

OBJECTIVE: To study the relationship between the susceptibility to two subtypes of Guillain-Barre syndrome(GBS) AIDP and AMAN and the frequency of HLA-class I and II alleles as well as to approach the characteristics of AIDP and AMAN patients in immune genetics. METHODS: A case control research was done on 31 AIDP and 33 AMAN and 132 health individuals. DNA was extracted from peripheral blood leucocytes by improved fast salting out. HLA genes were typed with DNA-based technology and PCR-sequence specific primers (PCR-SSP) method. RESULTS: HLA-A33 frequency of HLA-class I, and DR16 and DQ5 frequencies of HLA-class II showed a significant increase in AIDP group as compared with the control. Relative risk (RR) was 6.13, 8.28 and 3.47 respectively. Corrected probability (Pc) was 0.011, 0.014 and 0.025(P < 0.05). HLA-B15,B35 frequency of HLA-class I showed a significant increase in patients with AMAN as compared with the controls,RR was 4.09 and 7.08 respectively, Pc was 0.015 and 0.000 8 respectively. CONCLUSIONS: HLA-A33, DR15 and DQ5 may have association with susceptibility to AIDP; HLA-B15, B35 may have association with susceptibility to AMAN. HLA-class II genes were not found to have any association with AMAN.

Human PRRX1 and PRRX2 genes: cloning, expression, genomic localization, and exclusion as disease genes for Nager syndrome.

In this study, we extend our examination of the function of the Prrx1 (a.k.a Mhox, Prx1, K-2, and Pmx1) as well as Prrx2 (a.k.a. S8 and Prx2) genes by characterizing the expression of the human orthologs and their potential for causing specific human malformations. The expression pattern of PRRX2 and its close relative, PRRX1, were analyzed in human tissue by RT-PCR. Although the expression of these human genes is similar to their mouse orthologs, there are notable differences in expression. PRRX2 was detected in the human kidney and lung, whereas in mice and chickens neither of these tissues has been reported to express Prrx2. For PRRX1 the expression pattern was quite similar to other vertebrates, but the ratio of the two isoforms was reversed. To begin the search for the gene-disease connection, both genes were mapped to human chromosomes by FISH. The PRRX1 locus maps to 1q23, whereas the PRRX2 locus maps to 9q34.1. This localization, along with the recently described phenotypes of the gene-targeted Prrx1, Prrx2 and double mutant mice, enabled us to search the human disease databases for similar malformations. This examination suggested that mutations at the PRRX1 and/or PRRX2 loci could result in Nager Acrofacial Dysostosis (NAFD) syndrome. We obtained DNA samples from eight patients with NAFD, as well as two patients with Miller syndrome, and analyzed them for mutations in the PRRX1 and PRRX2 genes. The data excludes mutations in the presumed coding sequences of these genes from causing NAFD.