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PubMed1989

Identification and production of monoclonal antibodies against a discriminating protein molecule between B and D variants of encephalomyocarditis virus.

The protein profiles of two EMC virus variants B and D in the infected L929 fibroblast lysates were examined using one- and two-dimensional gel electrophoresis. Both variants yielded a protein molecule of similar molecular weight but differing in its isoelectric point (pI). The B variant lysate yielded a molecule with pI congruent to 7.5 whereas the same molecule from the D lysate focused at pI congruent to 5.2. A monoclonal antibody (MCA) produced against pI congruent to 5.2 fraction of the D variant successfully detected viral antigens in the D variant infected fibroblasts with only background cross reactivity with the B variant infected cells. This MCA also detected D viral antigen(s) in organ sections obtained from D but not from B variant infected mice. This study therefore suggests a clear shift in the pI of a 23 kD protein molecule serving as a possible discriminating antigen between the B and D variants of EMC virus.

Animals↗

PubMed1981

Glycopeptides from variant surface glycoproteins of Trypanosoma Brucei. C-terminal location of antigenically cross-reacting carbohydrate moieties.

Glycopeptides have been purified after trypsin or pronase cleavage of variant surface glycoproteins from five antigenic variants of one clone of Trypanosoma brucei. Each peptide has been characterised by its amino acid and sugar composition and partial or complete amino acid sequence. The peptides were assayed in an indirect precipitation radioimmunoassay for inhibition of precipitation of one variant surface glycoprotein by a heterologous antiserum raised against another variant. Two classes of glycopeptide were obtained, those which showed complete inhibition and those which had no inhibitory activity. The non-cross-reacting glycopeptides were all derived from internal sites in the polypeptide chain and had only mannose and glucosamine as the constituents of the glycosyl group with one exception which also contained galactose. The carbohydrate moieties involved in the immunological cross-reaction were found to be attached at or very close to the C-terminus of the protein and contained galactose, mannose and glucosamine. Considerable variation in the size and composition of these glycosyl moieties occurred between the variant glycoproteins and, in two cases, within individual glycoproteins. The immunological cross-reactivity was constant despite this oligosaccharide heterogeneity. There was significant amino acid sequence homology between glycopeptides from certain variants in contrast to the absence of homology observed previously for the N-terminal sequence of intact surface glycoproteins. Some C-terminal glycopeptide sequences suggest the occurrence of proteolytic processing subsequent to glycosylation and prior to variant surface glycoprotein isolation. The terminal amino acid (Asx or Ser) of all isolated variant surface glycoproteins was glycosylated.

Amino Acid Sequence↗

PubMed1982

Altered expression of ribokinase activity in Novikoff hepatoma variants.

Ribokinase, the first enzyme in ribose catabolism, is altered in its expression in ribose-utilizing Novikoff hepatoma variants. 90% of the variants selected for their ability to use D-ribose as a sole carbon source show a change in ribokinase activity. After non-selective growth, phenotypically unstable variants lose their altered expression and regain a parental form of expression of this enzyme. In the variants, ribokinase expression in non-inducible by the carbon source and is unaffected by the growth phase of the cells. However, ribokinase expression in both parental cells and variants is cell cycle-dependent. Parental Novikoff hepatoma cells have three peaks of ribokinase activity during the S, G2 and M phases. Variants are described which have high basal levels of ribokinase and only a single peak of enzymatic activity during the S phase. In addition to changes in the level of ribokinase, changes in the subcellular localization of the enzyme have been found in some variants. While the change in the level of ribokinase seems to be a property of the variant isolated, the change in subcellular location of ribokinase can be readily achieved by culture conditions.

Animals↗

PubMed1996

The E6 variant proteins E6I-E6IV of human papillomavirus 16: expression in cell free systems and bacteria and study of their interaction with p53.

Several species of alternatively spliced mRNAs are transcribed from the E6 gene region of human papillomavirus (HPV) 16. These have the coding capacity for either the full length E6 of 151 amino acids (aa) or four truncated variants, E6I-E6IV, of 43-64 aa. As the first step to identify the putative E6 variants and their functions, we generated cDNAs corresponding to the various E6 open reading frames (ORF) and examined their expression employing in vitro transcription/translation systems and the bacterial pET system. In wheat germ extract, in vitro translation resulted in the production of all five proteins, E6 and E6I-E6IV. These proteins were also expressed as stable fusion proteins from the pET16b and pET17 x b vectors in Escherichia coli. Mobilites of the E6 variant proteins on SDS-acrylamide gels were consistent with their predicted sizes. The authenticity of the synthesized proteins was confirmed by immunoprecipitation with specific antibodies directed against epitopes in the N-terminal portion of E6 as well as antibodies raised against the individual variant proteins produced in E. coli. In rabbit reticulocyte lysate, however, only the full length E6 and the E6IV variant were synthesized. This could be due to inefficient translation as well as lower stability of the short variants. E6I-III, in reticulocyte lysate (RTL). The ability of the E6 variants to associate with p53 and target its proteolytic degradation in vitro, was examined in coimmunoprecipitation assays, using in vitro synthesized proteins and monoclonal antibodies to p53. Results of these assays indicated that only the full length E6 efficiently binds to and promotes the degradation of p53. The E6 variants E6I-E6IV, although able to associate with p53 at a low efficiency, were unable to target its degradation.

Amino Acid Sequence↗

PubMed1988

Variants of HLA-DRw52 defined by T lymphocyte clones.

Polymorphism within the gene encoding the DRw52 allospecificity was studied with DRw52-specific proliferative T lymphocyte clones. Three clones, C6, E3 and ZUK16, were generated by intra-DRw52 priming in mixed lymphocyte culture and tested against an HLA-D homozygous reference cell panel. The reactivity of each clone could be specifically inhibited by anti-DR, but not anti-DQ or anti-DP, monoclonal antibodies. Clone C6 identified a DRw52 variant termed 52a that was predominantly expressed by HLA-B8,DR3+ and DRw13,Dw18+ cells. Clone E3 identified a variant termed 52b which was predominantly expressed by HLA-B18,DR3+,DRw11,Dw5+ and DRw14,Dw9+ cells. Clone ZUK16 identified a variant termed 52c which was predominantly expressed by DRw13,Dw19+ cells. The DRw52a, 52b and 52c variants correspond to the Dw24, Dw25 and Dw26 alleles defined by the WHO HLA 1987 Nomenclature Committee. Together, clones E3 and ZUK16 appeared to identify a fourth DRw52 variant termed 52d which was expressed by two cells, one DR3, Dw"3.3"+ and one DRw14,Dw"9.2"+. A fifth Drw52 variant termed 52e, expressed by a DRw13,Dw"OMW"+ cell, was suggested by the absence of reactivity with any of the three T cell clones. These data thus demonstrate the existence of three well-defined allelic variants of DRw52 and indicate that there are at least two additional variants. The recognition of these polymorphisms by alloreactive T cells provides one measure of their functional significance.

Alleles↗

PubMed1989

Prolactin variants in the rat adenohypophysis.

Prolactin (PRL) heterogeneity in the rat pituitary gland was first reported in 1978. Since then, multiple forms of the hormone in the rat pituitary gland have been reported by other investigators. Some of these variants have been ascribed to posttranslational modifications, while the origin of the others is as yet undefined. In this study, the nature, distribution and origin(s) of PRL size variants in the rat adenohypophysis were defined by Western blotting, Northern blot hybridization analysis and pulse-chase approaches. Thirteen structurally related variants, grouped into species with apparent molecular weights (Mr) 97-34,000, 31,000, 24,000 and 22-17,000, were consistently obtained on the basis of their electrophoretic mobilities in nonreducing polyacrylamide gels. Many of the Mr forms were disulphide-linked aggregates. Northern blot analysis suggested that the 24,000 monomeric PRL was encoded by the 0.9 kb mRNA species, while the 45,000 variant could be encoded by the 1.9 kb mRNA. Four PRL variants in the Mr range of 25-46,000 were synthesized concurrently by the mammotrophs in culture. Newly synthesized high Mr variants were also released into the medium and could be detected as early as 1 min after synthesis. Collectively these results suggest that structurally related PRL variants in the rat pituitary gland are due to a combination of posttranscriptional and posttranslational modification of a single gene product. In addition high Mr variants are preferentially secreted over low Mr forms, probably through an alternative secretory pathway.

Animals↗

PubMed1996

Expression of estrogen receptor variants in normal and neoplastic human uterus.

Estrogen receptor variants lacking internal exons and representing dominant positive and negative activity may be involved in the initiation and/or progression of endocrine dependent tumors. To assess the role of estrogen receptor in uterine disease, we have analyzed both normal and neoplastic uterine samples for the presence of variant estrogen receptors using the sensitive technique of RT-PCR and direct automated DNA sequencing of the amplified products. Our analysis was conducted to determine the presence of spliced variants lacking exons 3 through exon 8. We demonstrate that both the normal and neoplastic human uterus contains a number of spliced variants of the estrogen receptor that co-exist with the wild type receptor. Variants lacking exons 4, 5 and 7 but not exons 3 and 6 were detected. Also, a novel partial deletion in exon 8 was detected in both the normal and neoplastic tissues, although a total deletion of this exon was not observed. In addition another region of exon 8 deletion was found to be present in one tumor tissue which also contained an insertion within this region, however, other tumors did not contain this variant. In addition, double exon deletion variants were observed lacking exons 3 and 4, exons 4 and 5, and exon 7 with part of exon 8. Although our data represents a limited number of samples it suggests that splicing of the estrogen receptor message occurs in the normal physiological setting. There does not appear to be any association between the presence or absence of spliced variants of estrogen receptor and uterine tumor formation at the mRNA level.

Adenocarcinoma↗

PubMed2026

Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

RNA-binding proteins (RBPs) regulate gene expression, and a number of RBPs have been implicated in brain function and behavior. Here, we report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, encoding an RBP not previously linked to Mendelian disease. Thirteen individuals were identified through GeneMatcher. Their ELAVL2 variants include two structural, five nonsense, and six missense variants, supporting haploinsufficiency as the primary disease mechanism. The cohort presented with developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability, and difficulty with socialization. Three additional variants (two missense and one terminal exon truncation), each previously reported in a different large cohort study, were also included for follow-up investigations. We provide multiple lines of evidence linking variants in ELAVL2 to the observed neurodevelopmental and behavioral phenotypes. First, we show that common genetic variants in ELAVL2 are significantly associated with intelligence, motor development, sleep-related traits, and sociability in the general population. Drosophila loss-of-function models provide further independent evidence for a conserved role in the regulation of seizure-like behavior, sensory processing, and sleep. Molecular studies confirm that some of the missense variants are deleterious, leading to decreased protein levels. Together, our integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.

Humans↗

PubMed2026

CACNA1C Genetic Variants Differentially Affect Neuronal Networks Through Divergent Pathways.

BACKGROUND: CACNA1C encodes the pore-forming subunit of the L-type calcium channel Cav1.2. Common variants in CACNA1C are associated with psychiatric disorders, whereas rare single nucleotide variants cause CACNA1C-related disorder, a multisystem disorder with symptoms that include autism spectrum disorder (ASD), intellectual disability, and seizures. However, the cellular mechanisms linking CACNA1C dysfunction to neurodevelopmental phenotypes remain poorly understood. METHODS: We generated isogenic CACNA1C loss-of-function induced pluripotent stem cell lines and reprogrammed a line from an individual carrying a novel predicted gain-of-function variant (p.Ala1521Pro) in CACNA1C. Neuronal activity was assessed using multielectrode arrays, pharmacological manipulation, and gene expression analysis. Early developmental phenotypes were examined using quantitative reverse transcriptase polymerase chain reaction, immunocytochemistry, and RNA sequencing. RESULTS: Neurons carrying CACNA1C variants displayed opposing alterations in network dynamics, depending on variant type. Pharmacological and molecular assays indicated that these network differences were associated with dysregulated GABAergic (gamma-aminobutyric acidergic) signaling. Early developmental analysis revealed that loss of CACNA1C altered rosette morphology, CREB (cAMP response element binding protein) phosphorylation, and transcriptional programs related to axonogenesis and synaptic signaling, indicating effects on neuronal differentiation. The patient line exhibited opposing effects on rosette morphology and CREB signaling, reflecting variant-specific effects. CONCLUSIONS: These findings demonstrate that Cav1.2 regulates excitatory-inhibitory balance, network organization, and aspects of neurodevelopment. Divergent effects of CACNA1C variants highlight how altered Cav1.2 signaling contributes to variable neurodevelopmental phenotypes, including ASD and epilepsy, and establish a framework for defining CACNA1C variant effects in human neurons.

CACNA1C↗

PubMed2026

Twelve Japanese patients with POLG-related disorders: Population-specific genetic differences of POLG variants in Japan and Europe.

BACKGROUND: POLG encodes mitochondrial DNA (mtDNA) polymerase γ. Pathogenic POLG variants cause mitochondrial diseases, including progressive external ophthalmoplegia. POLG-related disorders are relatively common in Europe, possibly because of the high prevalence of carriers in the general population, but remain rare in Japan for unclear reasons. METHODS: We performed long-range PCR on mtDNA from skeletal muscle and/or peripheral blood from 3146 patients with suspected mitochondrial disease between 1993 and 2021. We selected 167 individuals with clinical features suggestive of POLG-related disorders for POLG gene analysis; all lacked pathogenic mtDNA point mutations, and most had multiple mtDNA deletions and/or a family history of mitochondrial disease. RESULTS: Among the 167 patients (median age: 52 years, range: 0-83 years, 11% pediatric cases), we identified 12 Japanese patients with POLG-related disorders and six POLG variants, including one novel variant. The six variants were p.Y955C, p.R943H, p.T599I, p.M299L, p.Y1210* (c.3626_3629dupGATA), and the novel variant p.F377S (c.1130T>C). Neither these six variants nor the 10 previously reported cases from Japan included the POLG variants that are more frequent in Europe. We also analyzed three population databases: two whole-genome sequencing databases covering 61,000 and 9850 Japanese individuals, respectively, and one global population database (gnomAD) covering 730,000 individuals worldwide. POLG variants that are more frequent in Europe were not detected in the Japanese databases or among East Asian individuals in gnomAD. CONCLUSIONS: Our findings suggest population-specific genetic differences in POLG between Japanese and European populations, explaining the lower frequency of POLG-related disorders in Japan.

CPEO↗

PubMed2004

No association between two MLH3 variants (S845G and P844L)and colorectal cancer risk.

Recently we identified a new variant, S845G, in the MLH3 gene in 7 out of 327 patients suspected of hereditary nonpolyposis colorectal cancer but not fulfilling the Amsterdam criteria and in 1 out of 188 control subjects. As this variant might play a role in causing sporadic colorectal cancer, we analyzed its prevalence in sporadic colorectal cancer patients. We analyzed a small part of exon 1 of the MLH3 gene, including the S845G variant, in germline DNA of 467 white sporadic colorectal cancer patients and 497 white controls. The S845G variant was detected in five patients and eight controls; the results thus indicate that this variant does not confer an increased colorectal cancer risk. Another variant (P844L) was clearly a polymorphism. Three other missense variants were rare and the sample size of the study was too small to conclude whether they are pathogenic. In conclusion, no association was observed between two MLH3 variants (P844L and S845G) and colorectal cancer risk.

Carrier Proteins↗

PubMed2005

Tissue distribution of a human Ca v 1.2 alpha1 subunit splice variant with a 75 bp insertion.

Mesenchymal stem cells from human bone marrow (MSC) express mRNA encoding the L-type Ca2+ channel Ca v 1.2 alpha1 subunit (alpha(1)1.2). We now describe a splice variant including an alternative exon of 75 bp in the region between exons 9 and 10, which we identified in MSC by semi-quantitative RT-PCR. With primers specific for variants including (+9*) or excluding the 75 bp insertion (-9*), we found comparable mRNA expression patterns in MSC and in primary cultures of related connective tissue cells (chondrocytes, osteoblasts and fibroblasts). Since culture conditions might have altered variant expression, we investigated mRNA levels in various native human tissue samples (cartilage, bone, fat, liver, kidney, aorta, bladder, cardiac ventricle and atrium, CNS). We found highest levels of the +9* variant in aorta, containing smooth muscle and connective tissue cells, but the variant was expressed in all tissues. We therefore hypothesized that broad expression of +9* might be linked to the presence of vasculature and/or connective tissue structures, rather than to tissue-specific parenchymal cells (e.g. cardiomyocytes). To test this hypothesis we separated human atrium into a cardiomyocyte-enriched fraction and a cardiomyocyte-depleted fraction. RT-PCR demonstrated significantly larger levels of the +9* variant in the non-cardiomyocyte fraction. The result was even more clear in single cell RT-PCR experiments, where the +9* variant was undetectable in cardiomyocytes but present in non-cardiomyocytes. We conclude that the +9* variant is present in all human tissues investigated so far, and suggest that expression in human atrium is associated with vascular smooth muscle and/or connective tissue cells.

Adult↗

PubMed2004

Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose.

BACKGROUND: Commonly occurring genetic variants in CYP2C9 are known to reduce catalytic activity and are associated with enhanced patient sensitivity to warfarin. Interethnic differences in warfarin dose requirement have been described in the Asian population, and we postulate that this could be related to genetic variants of CYP2C9 that are unique to ethnic groups. METHODS: We prospectively genotyped 125 patients who were receiving a stable daily warfarin dose to maintain international normalized ratio values between 2 and 3 through comprehensive sequencing of the promoter and coding regions of the CYP2C9 gene. RESULTS: The mean weight-adjusted warfarin maintenance dose was significantly lower for Malay and Chinese subjects than Indian subjects ( P <.001 and.014, respectively). Warfarin dose negatively correlated with age (r = -0.4, P <.001) but not with sex. Multiple variants were detected in the promoter, exonic, intronic, and 3'-untranslated regions of CYP2C9, of which 16 were novel, including 7 nonsynonymous exonic variants ( 208G>C, 374G>A, 485C>A, 895A>G, 1144C>T, 1190A>C, and 1362G>C ). CYP2C9*3, but not CYP2C9*2, was found in Chinese and Malay patients, and carriers of the CYP2C9*3 variant in Chinese ( P <.01) and Indian ( P <.01) patients, but not Malay patients ( P =.77), required less warfarin. The influence of the novel exonic variants on warfarin dose requirement was unclear, because they were rare, but the lower warfarin dose requirement for Chinese and Malay patients existed despite omission of individuals with any coding region variants from analysis. CONCLUSIONS: Interethnic differences in warfarin dosing in Asian subjects may result from other genetic, dietary, or environmental influences; however, these novel variants in the gene warrant further characterization through functional studies.

Adult↗

PubMed2006

Cytokine gene expression in Walker 256: a comparison of variants A (aggressive) and AR (regressive).

Two variants of this Walker 256 tumor have been previously reported as Walker 256 A and variant AR. The variant A has more aggressive property than variant AR and can induce systemic effects such as anorexia, sodium and water retention, followed by weight loss and death. The mechanisms involved in enhancing tumor regression and progression in this model are still incompletely understood. In the present study, serum and spleen mononuclear cells and tumor cells from animals inoculated with variants A and AR, were isolated to investigate the TGF-beta, IL-12, IFN-gamma and TNF-alpha and relationship with anemia, weight of animals, weight of spleen, volume of tumor and osmotic fragility compared with controls inoculated with Ringer Lactate. Results demonstrate that the group inoculated with variant A, compared to variant AR, shows high levels of TGF-beta gene expression in both tumor tissue and spleen cells, no expression of IFN-gamma and a progressive and higher levels of IL-12 in tumor tissue without inflammatory infiltrate visualized by optical microscopy. These results suggest that the aggressively of variant A is relate to cytokine modulation, facilitating the growth and escape of tumor cells. Furthermore, IL-12 seems to be constitutively expressed in both tumor lineage A and AR.

Anemia↗

PubMed2005

Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess.

OBJECTIVE: To determine whether frequencies of the mutations in the 21-hydroxylase (CYP21) gene and the G972R variant of the insulin receptor substrate-1 (IRS1) gene are increased in women with polycystic ovary syndrome (PCOS) and adrenal androgen (AA) excess. DESIGN: Prospective case-control study. SETTING: University reproductive endocrinology laboratory and outpatient clinic. PATIENT(S): Consecutive patients of non-Hispanic white race diagnosed with PCOS (n = 114) and healthy controls (n = 95). INTERVENTION(S): Blood and DNA sampling before hormonal therapy. MAIN OUTCOME MEASURE(S): Polycystic ovary syndrome patient and healthy control genotypes, with the CYP21 and IRS1 variants. RESULT(S): Fifty-four PCOS patients with (DHEAS >3000 ng/mL) and 55 without (DHEAS <2500 ng/mL) AA excess, respectively, were studied. Of 109 patients studied, 16 (14.7%) were found to be heterozygous carriers of mutations in the CYP21 gene. Of these 16, 10 (62.5%) had excessive AA secretion (i.e., excess DHEAS levels). Fifteen patients (13.8%) were found to be heterozygous carriers of the IRS1 variant; 9 (60.0%) of these 15 had excessive AA secretion. There were no significant differences in the allele frequency of CYP21 mutations or the IRS1 variant between PCOS patients with and without AA excess, and controls. None of the subjects were found to be homozygous carriers of CYP21 mutations or the IRS1 variant. Combined heterozygosity for CYP21 mutations and the IRS1 variant was limited to women with PCOS and excessive AA (n = 3). CONCLUSION(S): The G972R variant of the IRS1 gene might represent a modifier locus among women who are heterozygous carriers of CYP21 mutations, potentially increasing their risk of developing AA excess in PCOS. Nonetheless, this IRS1 variant and CYP21 mutations seem to play a limited role in the development of PCOS in the population studied.

Adrenal Glands↗

PubMed2006

Identification and characterization of four splicing variants of ovine POU1F1 gene.

Expression of POU1F1 gene, a member of the POU homeodomain family of transcription factors, is necessary for normal differentiation, development and survival of three anterior pituitary cell types (thyrotrophs, somatotrophs and lactotrophs) and for the proper expression of growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH) genes and POU1F1 gene itself. Alternative splicing forms of this gene have been reported in different species, with few functional studies. Apart from the POU1F1-Wild-type with the expected length, in this work we isolated three additional splicing variants: POU1F1-beta, with a 78 bp insert in the trans-activation domain; POU1F1-gamma that lacks exon 3 and POU1F1-delta that lacks exons 3, 4 and 5. Four different protein isoforms were also detected by Western blot in the sheep pituitary tissue. Functional assays were performed to study the trans-activation of GH and PRL promoters by the splicing variants. Regarding the PRL promoter, the beta variant presented only 12% of the Wild-type trans-activation capacity. Variants gamma and delta showed no capacity to trans-activate PRL promoter. Both gamma and delta variants acted as repressors of Wt, reducing significantly the trans-activation made by Wt alone (p<0.05). Concerning the GH promoter, the beta variant presented a trans-activation capacity 10% higher than Wt. Wt and beta variants strongly interact in the activation of GH promoter doubling the trans-activation potential of Wt. Variants gamma and delta showed no capacity to trans-activate the GH promoter and both acted as repressors, reducing significantly (p<0.001) the trans-activation performed by Wt. This work presents, for the first time, the characterization of four splicing forms of Ovis aries POU1F1 gene.

Alternative Splicing↗

PubMed2025

Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome.

PURPOSE: To quantify the impact of noncanonical FBN1 splice site variants in undiagnosed Marfan syndrome (MFS), a connective tissue disorder associated with skeletal abnormalities and familial thoracic aortic aneurysm disease (FTAAD). METHODS: A systematic analysis of ultrarare FBN1 variants was performed using genome sequencing data from the 100,000 Genomes Project. Variants were annotated with SpliceAI and the significance of enrichment among individuals with FTAAD was assessed using Fisher's exact test. Experimental validation used RNA sequencing, reverse transcriptase polymerase chain reaction, minigene constructs, and replication analysis was with data from UK Biobank. RESULTS: Using aggregate data for 78,195 individuals, we identified 13,864 singleton single-nucleotide variants in FBN1 of which 21 were predicted to affect splicing (SpliceAI > 0.5). Incidence of candidate splice variants in individuals recruited with FTAAD (9/703) was significantly elevated compared with that seen in non-FTAAD participants (12/77,492; odds ratio = 84, P = 9.7 × 10-14). Additional analysis uncovered a further 14 families harboring 11 different FBN1 splice variants. A total of 20 candidate splice variants in 23 families were identified, of which 70% lay beyond the ±8 splice regions. RNA testing confirmed the predicted splice aberration in 16 of 20 and for 9 of 20, pseudoexonization was the likely splicing anomaly. CONCLUSION: Our findings indicate that noncanonical splice variants may account for approximately 3% of families with undiagnosed FTAAD, highlighting the importance of incorporating analysis of introns and confirmatory RNA testing into genetic testing for Marfan syndrome.

Humans↗

PubMed2004

Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing.

OBJECTIVES: The purpose of this study was to determine the prevalence and spectrum of nonsynonymous polymorphisms (amino acid variants) in the cardiac sodium channel among healthy subjects. BACKGROUND: Pathogenic mutations in the cardiac sodium channel gene, SCN5A, cause approximately 15 to 20% of Brugada syndrome (BrS1), 5 to 10% of long QT syndrome (LQT3), and 2 to 5% of sudden infant death syndrome. METHODS: Using single-stranded conformation polymorphism, denaturing high-performance liquid chromatography, and/or direct DNA sequencing, mutational analysis of the protein-encoding exons of SCN5A was performed on 829 unrelated, anonymous healthy subjects: 319 black, 295 white, 112 Asian, and 103 Hispanic. RESULTS: In addition to the four known common polymorphisms (R34C, H558R, S1103Y, and R1193Q), four relatively ethnic-specific polymorphisms were identified: R481W, S524Y, P1090L, and V1951L. Overall, 39 distinct missense variants (28 novel) were elucidated. Nineteen variants (49%) were found only in the black cohort. Only seven variants (18%) localized to transmembrane-spanning domains. Four variants (F1293S, R1512W, and V1951L cited previously as BrS1-causing mutations and S1787N previously published as a possible LQT3-causing mutation) were identified in this healthy cohort. CONCLUSIONS: This study provides the first comprehensive determination of the prevalence and spectrum of cardiac sodium channel variants in healthy subjects from four distinct ethnic groups. This compendium of SCN5A variants is critical for proper interpretation of SCN5A genetic testing and provides an essential hit list of targets for future functional studies to determine whether or not any of these variants mediate genetic susceptibility for arrhythmias in the setting of either drugs or disease.

Bundle-Branch Block↗