It has recently been suggested that short expansions of CAG repeat in the gene
ATXN
-
2
causing SCA2 (spinocerebellar ataxia type 2) are associated with an increased risk of amyotrophic lateral ...sclerosis (ALS) in the populations of the USA and northern Europe. In this study, we investigated the role of
ATXN
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2
in Italian patients clinically diagnosed with ALS and characterized the molecular structure of
ATXN
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2
expansions. We assessed the size of the CAG repeat in
ATXN
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2
exon 1 in 232 Italian ALS patients and 395 matched controls.
ATXN
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2
expanded alleles containing >30 repeats have been observed in seven sporadic ALS patients (3.0%), while being absent in the controls (
p
= 0.00089). Four out of the seven patients had an
ATXN
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2
allele in the intermediate-fully pathological range: one with 32 repeats, 2 with 33 repeats and 1 with 37 repeats, accounting for 1.7% of the ALS cohort. Sequencing of expanded (
>
32) alleles showed that they were all interrupted with at least one CAA triplet.
ATXN
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2
alleles with the same length and structure have been reported in SCA2 patients with parkinsonism or in familial and sporadic Parkinson. Conversely, the phenotype of the present patients was typically ALS with no signs or symptoms of ataxia or parkinsonism. In conclusion, the findings of
ATXN
-
2
expansions in pure ALS cases suggest that ALS may be a third phenotype (alongside ataxia/parkinsonism and pure Parkinson) associated with
ATXN
-
2
interrupted alleles.
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance. In a genome-wide scan using 85,042 SNPs, we ...identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 × 10−10; OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Δ2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point-site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell-receptor signaling and B-cell hyperactivity characteristic of this disease.
Alpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson's disease (PD). A previous study showed that a variant of the alpha-synuclein gene (
), namely the ...263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients.
We recruited and genotyped for
Rep1 426 PD patients with age at onset ≥40 years and disease duration ≥4 years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations, and dementia using a multivariate Cox's proportional hazards regression model.
Rep1 263 carriers showed significantly increased risk of both dementia (HR = 3.03) and visual hallucinations (HR = 2.69) compared to 263 non-carriers. Risk of motor complications did not differ in the two groups.
Rep1 263 allele is associated with a worse cognitive outcome in PD.
Abstract A hexanucleotide repeat expansion (RE) in C9ORF72 gene was recently reported as the main cause of amyotrophic lateral sclerosis (ALS) and cases with frontotemporal dementia. We screened ...C9ORF72 in a large cohort of 259 familial ALS, 1275 sporadic ALS, and 862 control individuals of Italian descent. We found RE in 23.9% familial ALS, 5.1% sporadic ALS, and 0.2% controls. Two cases carried the RE together with mutations in other ALS-associated genes. The phenotype of RE carriers was characterized by bulbar-onset, shorter survival, and association with cognitive and behavioral impairment. Extrapyramidal and cerebellar signs were also observed in few patients. Genotype data revealed that 95% of RE carriers shared a restricted 10-single nucleotide polymorphism haplotype within the previously reported 20-single nucleotide polymorphism risk haplotype, detectable in only 27% of nonexpanded ALS cases and in 28% of controls, suggesting a common founder with cohorts of North European ancestry. Although C9ORF72 RE segregates with disease, the identification of RE both in controls and in patients carrying additional pathogenic mutations suggests that penetrance and phenotypic expression of C9ORF72 RE may depend on additional genetic risk factors.
Abstract We have attempted to replicate a recently reported association of polymorphism rs10260404, in the Dipeptidyl-peptidase 6 gene ( DPP6 ), with susceptibility to amyotrophic lateral sclerosis ...(ALS) in a large independent Italian cohort of 904 cases and 1036 controls. Minor allele frequency was 0.38 in cases and 0.39 in controls and no evidence of association with ALS was observed ( P = 0.638). Our negative results agree with those recently reported in additional Polish and Italian cohorts.
Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was ...to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and
functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in
, a gene coding for a protein of an unknown function (
< 10
). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (
= 0.0093 and
= 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (
= 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (
= 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases.
neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 ...signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02).
we identified one promoter SNP (rs2530547 -103) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 Ile107Asn, rs34705969 Cys197Phe, rs727162 Arg241Ser), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk.
these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.
We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the ...predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.1,2 We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1+/− mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.
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•Intronic deletions in VANGL1 are associated with risks of glomerulonephritis in SLE•Vangl1+/− mice develop spontaneous deposition of immunoglobulin in glomeruli•Vangl1+/− mice do not develop glomerulonephritis despite antibody deposition•Immunoglobulin deposition in Vangl1+/− occurs in a kidney-intrinsic manner
The organ specificity risks of lupus nephritis are unclear. Jiang et al. identify a common intronic deletion in VANGL1 that increases risks of nephritis in SLE patients. Vangl1+/− mice develop spontaneous deposition of immunoglobulin in the kidney without glomerulonephritis in a kidney intrinsic manner.
A recent study by Wang et al. (2016a) claims that the low-frequency variant NR1H3 p.Arg415Gln is sufficient to cause multiple sclerosis in certain individuals and determines a patient’s likelihood of ...primary progressive disease. We sought to replicate this finding in the International MS Genetics Consortium (IMSGC) patient collection, which is 13-fold larger than the collection of Wang et al. (2016a), but we find no evidence that this variant is associated with either MS or disease subtype. Wang et al. (2016a) also report a common variant association in the region, which we show captures the association the IMSGC reported in 2013. Therefore, we conclude that the reported low-frequency association is a false positive, likely generated by insufficient sample size. The claim of NR1H3 mutations describing a Mendelian form of MS—of which no examples exist—can therefore not be substantiated by data. This Matters Arising paper is in response to Wang et al. (2016a), published in Neuron. See also the related Matters Arising paper by Minikel and MacArthur (2016) and the response by Wang et al. (2016b), published in this issue.
•We attempt to replicate Wang et al.’s observation that NR1H3 p.Arg415Gln drives multiple sclerosis risk•In a 13-fold larger sample, we find no evidence of association to either MS risk or clinical course•We conclude their result is a false positive due to insufficient statistical rigor and flawed logic
The IMSGC find no evidence in >69,000 samples that NR1H3 p.Arg415Gln causes multiple sclerosis in families and determines clinical course, as reported by Wang et al. This refutes the initial claim that NR1H3 mutations describe a Mendelian form of MS.
Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system caused by an interplay of environmental and genetic factors. The only genetic region that has been clearly ...demonstrated by linkage and association studies to contribute to MS genetic susceptibility is the human leukocyte antigen (HLA) system. The majority of HLA population studies in MS have focused on Caucasians of Northern European descent, where the predisposition to disease has been consistently associated with the class II DRB1*1501-DQA1*0102-DQB1*0602 haplotype. A positive association with DR4 was detected in Sardinians and in other Mediterranean populations. Moreover DR1, DR7, DR11 have been found to be protective in several populations. Systematic searches aimed at identifying non-HLA susceptibility genes were undertaken in several populations by means of linkage studies with microsatellite markers distributed across the whole genome. The conclusion of these studies was that there is no major MS locus, and genetic susceptibility to the disease is most likely explained by the presence of different genes each conferring a small contribution to the overall familial aggregation. The involvement of several candidate genes was tested by association studies, utilizing either a population-based (case control) or a family-based (transmission disequilibrium test) approach. Candidate genes were selected mainly on the basis of their involvement in the autoimmune pathogenesis and include immunorelevant molecules such as cytokines, cytokine receptors, immunoglobulin, T cell receptor subunits and myelin antigens. With the notable exception of HLA, association studies met only modest success. This failure may result from the small size of the tested samples and the small number of markers considered for each gene. New tools for large scale screening are needed to identify genetic determinants with a low phenotypic effect. Large collaborative studies are planned to screen several thousands of patients with MS with several thousands of genetic markers. The tests are increasingly based on the DNA pooling procedure.
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