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PubMed2025

Whole-genome sequencing, as a powerful diagnostic tool in hearing loss, reveals novel variants in PTPRQ missed by whole-exome sequencing.

BACKGROUND/OBJECTIVES: Hearing loss (HL) is one of the most common congenital disorders, affecting 1-2 in 1,000 newborns. Modern genetic diagnostics using large gene panels and/or whole exome analysis (WES) can identify disease-causing mutations in 25-50 % of patients, with higher solve rates in individuals with earlier onset. RESULTS: Here, we used whole-genome sequencing (WGS) to reanalyze 14 index patients/families who remained without genetic diagnosis by WES. We were able to identify the genetic cause of HL in 6 families (43 %). Two families were diagnosed with DFNB84A caused by compound heterozygous recessive mutations in PTPRQ. Three of the four underlying variants, including a structural variant, a deep intronic variant, and a splice variant, escaped detection by WES. Minigene assays confirmed the pathogenicity of the intronic and the splice variants. In addition, we used protein 3D structure prediction and rigid ligand docking to study the pathogenicity of variants that escape nonsense-mediated decay. CONCLUSION: In our study, we present four novel variants in PTPRQ, three of which were detected only by WGS. To our knowledge, we report here the first pathogenic deep intronic PTPRQ variant causing HL. Our results suggest that the mutational spectrum of PTPRQ is not well covered by standard WES and that PTPRQ-associated hearing loss may be more frequent than previously thought. WGS provides an additional layer of information in the diagnostics of HL.

Humans↗

PubMed1998

[Levels of neuropeptide Y and thromboxane B2 in patients with variant angina].

One of the causes of coronary artery spasm in patients with variant angina could be a disturbed interaction between the vasodilating action of endothelial derived relaxing factor and the vasospastic action of neuropeptide Y and thromboxane B2. The aim of this study was a verification of the participation of neuropeptide Y and thromboxane B2 in etiopathogenesis of the coronary artery spasm in patients with variant angina. The survey was made in 38 patients with variant angina and in 18 patients with chronic stable angina pectoris. The control group consisted of 20 healthy persons. Before the hyperventilation test, during which the person under test has been breathing with a frequency of 40/minute through 5 minutes, the Tris (tromethamol) of pH = 10.5 has been given in intravenous infusion lasting for 5 minutes. The neuropeptide Y and thromboxane B2 plasma levels have been determined just before the hyperventilation test, just after the termination of the test and 10 minutes after the termination of the test. Neuropeptide Y and thromboxane B2 plasma levels have been determined with a radioimmunologic method. It has been recorded that during the hyperventilation test in all of the 38 patients with variant angina the clinical and the electrocardiographic symptoms of the coronary artery spasm have appeared--but these have not appeared in patients with chronic stable angina pectoris and in healthy persons. The level of neuropeptide Y in patients with variant angina before the test, just at its end and as well as 10 min. after completing of the hyperventilation test, was significantly higher compared with the level in patients with chronic stable angina pectoris and controls. Contrary to chronic stable angina pectoris patients and controls, in variant angina group the level of neuropeptide Y increased rapidly at the end of the test and further elevation in neuropeptide Y level was observed 10 min. after the test. There was no difference in basal thromboxane B2 levels between angina patients and controls. At the end of hyperventilation test in variant angina group thromboxane B2 level significantly increased and remained on this level until 10 min. after the test. Significant increase of neuropeptide Y and thromboxane B2 plasma levels in variant angina patients during artery coronary spasm induced by hyperventilation test suggests the contribution of these humoral factors to the pathogenesis of vasospastic episodes in angina patients.

Adult↗

PubMed2002

Diuretic therapy, the alpha-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension.

CONTEXT: A genetic variant in alpha-adducin has been associated with renal sodium reabsorption and salt-sensitive hypertension. Whether this genetic variant modifies the effect of diuretic therapy on the incidence of myocardial infarction (MI) and stroke is unknown. OBJECTIVES: To estimate the interaction between alpha-adducin and diuretic therapy on the risk of MI or stroke. Specifically, we hypothesized that in participants with treated hypertension, the risk of MI or stroke associated with diuretic use would be lower in carriers of the adducin variant than in carriers of the adducin wild-type genotype. DESIGN, SETTING, AND PARTICIPANTS: Population-based case-control study of patients enrolled in a health maintenance organization, treated pharmacologically for hypertension, and genotyped as homozygous carriers of the adducin wild-type genotype or carriers of 1 or 2 copies of the Trp460 variant allele. Cases had a first nonfatal MI (n = 206) or stroke (n = 117) between January 1995 and December 1998. Controls (n = 715) were a stratified random sample of pharmacologically treated hypertensive patients who were matched to MI cases by age, sex, and calendar year. MAIN OUTCOME MEASURE: Risk of the combined outcome of first nonfatal MI or stroke. RESULTS: The adducin variant was present in more than one third of the participants. Among the 653 carriers of the adducin wild-type genotype, diuretic therapy was not associated with the risk of MI or stroke (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.78-1.52). Among the 385 carriers of the adducin variant allele, diuretic therapy was associated with a lower risk of the combined outcome of MI and stroke than other antihypertensive therapies (OR, 0.49; 95% CI, 0.32-0.77). The OR in carriers of the adducin variant was less than half of the OR in carriers of the wild-type genotype (P =.005). The case-control synergy index (SI) was 0.45 (95% CI, 0.26-0.79) for the combined outcome of MI and stroke. The point estimates of the diuretic-adducin interaction were similar in separate analyses of MI (SI, 0.41; 95% CI, 0.21-0.80) and stroke (SI, 0.53; 95% CI, 0.24-1.19). The diuretic-adducin interaction was not confounded by traditional cardiovascular risk factors, was specific to diuretic therapy but not present for other major antihypertensive drug classes, and did not differ substantially between subgroups defined by age, sex, race, diabetes, and history of cardiovascular disease. CONCLUSIONS: In carriers of the adducin variant, diuretic therapy was associated with a lower risk of combined MI or stroke than other antihypertensive therapies. If these findings are confirmed in other studies, this large subgroup of the hypertensive population may be especially likely to benefit from low-dose diuretic therapy.

Aged↗

PubMed2002

Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.

CONTEXT: Warfarin is a commonly used anticoagulant that requires careful clinical management to balance the risks of overanticoagulation and bleeding with those of underanticoagulation and clotting. The principal enzyme involved in warfarin metabolism is CYP2C9, and 2 relatively common variant forms with reduced activity have been identified, CYP2C9*2 and CYP2C9*3. Patients with these genetic variants have been shown to require lower maintenance doses of warfarin, but a direct association between CYP2C9 genotype and anticoagulation status or bleeding risk has not been established. OBJECTIVE: To determine if CYP2C9*2 and CYP2C9*3 variants are associated with overanticoagulation and bleeding events during warfarin therapy. DESIGN AND SETTING: Retrospective cohort study conducted at 2 anticoagulation clinics based in Seattle, Wash. PARTICIPANTS: Two hundred patients receiving long-term warfarin therapy for various indications during April 3, 1990, to May 31, 2001. Only patients with a complete history of warfarin exposure were included. MAIN OUTCOME MEASURES: Anticoagulation status, measured by time to therapeutic international normalized ratio (INR), rate of above-range INRs, and time to stable warfarin dosing; and time to serious or life-threatening bleeding events. RESULTS: Among 185 patients with analyzable data, 58 (31.4%) had at least 1 variant CYP2C9 allele and 127 (68.6%) had the wild-type (*1/*1) genotype. Mean maintenance dose varied significantly among the 6 genotype groups (*1/*1 [n = 127], *1/*2 [n = 28], *1/*3 [n = 18], *2/*2 [n = 4], *2/*3 [n = 3], *3/*3 [n = 5]) (by Kruskall-Wallis test, chi(2)(5) = 37.348; P<.001). Compared with patients with the wild-type genotype, patients with at least 1 variant allele had an increased risk of above-range INRs (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.03-1.90). The variant group also required more time to achieve stable dosing (HR, 0.65; 95% CI, 0.45-0.94), with a median difference of 95 days (P =.004). In addition, although numbers were small for some genotypes, representing potentially unstable estimates, patients with a variant genotype had a significantly increased risk of a serious or life-threatening bleeding event (HR, 2.39; 95% CI, 1.18-4.86). CONCLUSIONS: The results of our study suggest that the CYP2C9*2 and CYP2C9*3 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving warfarin.

Aged↗

PubMed2024

Bidirectional Risk Modulator and Modifier Variant of Dilated and Hypertrophic Cardiomyopathy in BAG3.

IMPORTANCE: The genetic factors that modulate the reduced penetrance and variable expressivity of heritable dilated cardiomyopathy (DCM) are largely unknown. BAG3 genetic variants have been implicated in both DCM and hypertrophic cardiomyopathy (HCM), nominating BAG3 as a gene that harbors potential modifier variants in DCM. OBJECTIVE: To interrogate the clinical traits and diseases associated with BAG3 coding variation. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study in the Penn Medicine BioBank (PMBB) enrolling patients of the University of Pennsylvania Health System's clinical practice sites from 2014 to 2023. Whole-exome sequencing (WES) was linked to electronic health record (EHR) data to associate BAG3 coding variants with EHR phenotypes. This was a health care population-based study including individuals of European and African genetic ancestry in the PMBB with WES linked to EHR phenotypes, with replication studies in BioVU, UK Biobank, MyCode, and DCM Precision Medicine Study. EXPOSURES: Carrier status for BAG3 coding variants. MAIN OUTCOMES AND MEASURES: Association of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes. RESULTS: In PMBB (n = 43 731; median [IQR] age, 65 [50-76] years; 21 907 female [50.1%]), among 30 324 European and 11 198 African individuals, the common C151R variant was associated with decreased risk for DCM (odds ratio [OR], 0.85; 95% CI, 0.78-0.92) and simultaneous increased risk for HCM (OR, 1.59; 95% CI, 1.25-2.02), which was confirmed in the replication cohorts. C151R carriers exhibited improved longitudinal outcomes compared with noncarriers as assessed by age at death (hazard ratio [HR], 0.85; 95% CI, 0.74-0.96; median [IQR] age, 71.8 [63.1-80.7] in carriers and 70.3 [61.6-79.2] in noncarriers) and heart transplant (HR, 0.81; 95% CI, 0.66-0.99; median [IQR] age, 56.7 [46.1-63.1] in carriers and 55.6 [45.2-62.9] in noncarriers). C151R was associated with reduced risk of DCM (OR, 0.42; 95% CI, 0.24-0.74) and heart failure (OR, 0.27; 95% CI, 0.14-0.50) among individuals harboring truncating TTN variants in exons with high cardiac expression (n = 358). CONCLUSIONS AND RELEVANCE: BAG3 C151R was identified as a bidirectional modulator of risk along the DCM-HCM spectrum, as well as an important genetic modifier variant in TTN-mediated DCM. This work expands on the understanding of the etiology and penetrance of DCM, suggesting that BAG3 C151R is an important genetic modifier variant contributing to the variable expressivity of DCM, warranting further exploration of its mechanisms and of genetic modifiers in DCM more broadly.

Humans↗

PubMed2026

Efficacy of Acoramidis in Wild-Type and Variant Transthyretin Amyloid Cardiomyopathy: Results From ATTRibute-CM and Its Open-Label Extension.

IMPORTANCE: Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive disease caused by misfolded transthyretin (TTR), occurs as wild-type (ATTRwt-CM) or variant (ATTRv-CM) forms. p.Val142Ile is the most common variant in the US, linked to rapid progression and increased mortality. Acoramidis achieves near-complete (≥90%) TTR stabilization and showed clinical benefit in the 30-month ATTRibute-CM trial and through month 42 in the ongoing open-label extension (OLE). OBJECTIVE: To evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile). DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, phase 3, randomized placebo-controlled study took place from April 2019 to May 2023 with ongoing OLE (month 42). ATTRibute-CM enrolled 632 participants with ATTR-CM; 611 of 632 were included in the modified intention-to-treat (mITT) population. There were 380 participants who continued into the OLE. These data were analyzed from January 2025 to July 2025. INTERVENTIONS: Oral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment. MAIN OUTCOMES AND MEASURES: All-cause mortality (ACM), cardiovascular-related hospitalizations (CVH), serum TTR, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N-terminal pro B-type natriuretic peptide in participants with ATTRwt-CM and ATTRv-CM. Post-hoc analyses were conducted in variant subgroups, including p.Val142Ile. RESULTS: Overall, 552 participants with wild-type ATTR-CM (mean [SD] age, 78 [6.3] years; 92.0% male and 8.0% female) and 59 participants with variant ATTR-CM (mean [SD] age, 73 [7.7] years; 77.3% male and 22.7% female) were randomized (mITT population), including 35 with p.Val142Ile. Consistent efficacy was observed in wild-type and variant subgroups for ACM/CVH through month 30 and ACM through month 42. At month 30, acoramidis reduced the risk of ACM/first CVH vs placebo by 31% in ATTRwt-CM (hazard ratio [HR], 0.69; 95% CI, 0.52-0.90; P = .007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; P = .01). ACM was reduced through month 42 with HRs of 0.70 (95% CI, 0.50-0.98; P = .04) and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRwt-CM and ATTRv-CM groups, respectively. Consistent treatment benefit was observed in participants with ATTRwt-CM and ATTRv-CM for secondary end points. Within variant subgroups (p.Val142Ile vs non-p.Val142Ile), consistent treatment benefits were observed for ACM/CVH through month 30 and ACM through month 42. CONCLUSIONS AND RELEVANCE: The beneficial effect of acoramidis was observed consistently in ATTRwt-CM and ATTRv-CM groups. These hypothesis-generating results indicate that further studies are warranted to better characterize the therapeutic benefit of acoramidis in variant subgroups. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT03860935; NCT04988386.

Humans↗

PubMed1996

Immunohistochemical detection of adhesion molecule CD44 splice variants in lymph node metastases of cervical cancer.

Expression of specific cell adhesion molecule CD44 isoforms (splice variants) has been shown to be associated with poor prognosis in human cervical cancer. We used 3 different variant exon sequence-specific murine monoclonal antibodies (MAbs) to epitopes encoded by exons v5, v6 and v7-v8 of human variant CD44 to study the expression of CD44 splice variants in 35 primary squamous-cell carcinomas of the cervix and pelvic lymph node metastases by means of immunohistochemistry. Primary tumors showed expression of CD44 splice variants CD44v5, CD44v6 and CD44v7-8 in 93%, 73% and 33% of cases, respectively. Lymph node metastases expressed CD44v5, CD44v6 and CD44v7-8 in 83%, 53% and 21% of cases, respectively. Tumors with expression of CD44v6 in pelvic lymph node metastases showed metastatic spread to 2 or more pelvic lymph nodes significantly more often compared to patients without expression of splice variant CD44v6. Patients suffering from tumors with lymph node metastases expressing splice variant CD44v6 had a poorer recurrence-free survival compared to patients without CD44v6 expression in lymph node metastases, but this trend was not statistically significant. Expression of CD44 splice variants containing epitopes encoded by exon v6 in primary tumors and pelvic lymph node metastases of cervical cancer patients is consistent with a prominent role of CD44 in the process of metastasis formation.

Adult↗

PubMed2026

Third Patient With Biallelic Variants in SMAD6 With an Overlapping Phenotype: Developmental Delays, Dysmorphic Features, and Cardiovascular Abnormalities.

SMAD6 encodes an inhibitory SMAD protein that modulates BMP and TGF-β signaling. Heterozygous pathogenic variants in SMAD6 have been primarily associated with aortic valve disease, radioulnar synostosis, and nonsyndromic sagittal and metopic synostosis. However, only two syndromic patients with biallelic variants have been reported in the literature. We report a 4-year-old girl with neurodevelopmental delays, dysmorphic features, complex congenital heart disease, renal asymmetry, and arterial tortuosity. Whole exome sequencing showed two homozygous SMAD6 variants of uncertain significance: c.161G>T (p.Gly54Val) and c.1A>G (p.Met1?). This is the third patient with biallelic SMAD6 variants associated with skeletal changes, more complex cardiovascular phenotype, facial dysmorphism, and novel arterial abnormalities. This suggests biallelic variants may cause a distinct and potentially more severe autosomal recessive syndrome. Functional investigation is needed to determine the molecular consequences of biallelic SMAD6 variants and to inform variant classification and mechanism. This report characterizes a potential unique genetic syndrome associated with biallelic SMAD6 variants, highlighting the importance of additional sequencing, vascular imaging, and multidisciplinary care coordination for these patients.

SMAD6↗

PubMed1979

Electrophoretic variants in three Amerindian tribes: the Baniwa, Kanamari, and Central Pano of western Brazil.

Data are presented on electrophoretic variants of 25 polypeptides found in the blood serum and erythrocytes, in 812 individuals from three Amerindian tribes, the Pano, the Baniwa, and the Kanamari. Two "private polymorphisms" were encountered, of PEPB in the Pano and CAII in the Baniwa. A single example of a different PEPB variant was encountered in the Baniwa, and two possible examples of an unstable variant of HGB A2 in the Kanamari. In addition, the well-known A variant of ACP1, the Duarte variant of GALT, the 2 variant of Hp and the 2 variant of PGM1 occurred in polymorphic proportions in all three tribes, and the TFDChi variant was present as a polymorphism in the Baniwa. These data have recently been incorporated into a treatment which concludes that the eight electrophoretically-defined "private polymorphisms" thus far encountered in Amerindian tribes can be explained by a mutation pressure of 0.7 x 10(-5)/locus/generation on the assumption of neutrality of the phenotypes in question (Neel and Thompson, '78).

Asian People↗

PubMed1994

Monoclonal IgA class-switch variants against bacterial surface antigens: molecular forms and transport into murine respiratory secretions.

The present study describes a new model for passive immunization of the respiratory tract with IgA in comparison to other isotypes. Monoclonal IgA-isotype-switch variants were isolated from different IgG-producing hybridoma clones specific for surface epitopes of bacterial respiratory tract pathogens. Analysis of the molecular form of the IgA variants revealed the simultaneous production of monomeric, dimeric and higher polymeric IgA by a single-cell line with predominance of the polymeric forms. The specificities of the IgA variants were identical to the parent IgG antibodies as demonstrated by inhibition experiments. The IgA variant antibodies were separated into monomers and polymers by gel filtration. Intravenous injection of the different molecular forms of IgA and of IgG into mice were used to investigate the transport characteristics of IgA into murine upper and lower respiratory tract secretions by the physiological route in comparison to IgG. Polymeric IgA variant, monomeric IgA variant and IgG were detected in immunologically active form in both nasal secretion and bronchoalveolar fluid as evidenced by binding to their antigens in an enzyme-linked immunosorbent assay. The relative contribution of the specific exogenous monoclonal IgA and monoclonal IgG to total IgA and IgG, respectively, was determined in secretions. Comparison of the secretion to serum transport ratios clearly indicates selective transport of polymeric IgA variant into nasal secretions relative to IgG parent antibody. Molecular and functional characteristics of the IgA variants make them ideal for passive mucosal immunization experiments and identification of protective epitopes in mucosal immunity.

Animals↗

PubMed2002

Involvement of ATM missense variants and mutations in a series of unselected breast cancer cases.

It has been proposed that women carrying heterozygous mutations of the ATM gene could be at increased risk of developing breast cancer. However, data in the literature are contrasting and no firm conclusion has been reached. Our aim was to verify whether ATM inactivation could play a role in breast tumor development. Following the classical tumor suppressor inactivation scheme, tumors showing loss of heterozygosity (LOH) at the ATM locus should present an increased proportion of mutated ATM forms. We screened a cohort of 173 nonselected primary breast tumors for LOH in a 4 cM region at 11q23 spanning the ATM gene. We analyzed 25 tumors presenting LOH within the ATM locus for mutations in the ATM coding sequence using an RT-PCR-SSCP approach. Five patients were found to bear a coding missense variant, out of which four corresponded to a frequent polymorphism in exon 39. One patient presented a previously unreported variant in exon 19 (2614C>T) resulting in a nonconservative change (Pro>Ser) at aa 872. This variant was not found in any of the other 172 patients nor in 63 healthy controls tested, indicating that it is a rare ATM variant. LOH involved the ATM wild-type allele in the tumor presenting variant 2614. However, because the ATM gene presents a relatively large number of rare coding polymorphism it is difficult, in the absence of familial data, to be conclusive on the significance of this variant. Searching for further variants in exons 19 and 39 in the whole set of 173 breast tumors, we found one tumor showing an acquired deletion of four bases in the ATM gene. Somatic mutations affecting the ATM gene thus seem rare in breast cancer. In our cohort of breast cancer patients, tumors presenting LOH at the ATM locus did not show an increased frequency of sequence variants. Furthermore, allelic imbalance profiles in a 4-cM region of chromosome arm 11q spanning the ATM locus revealed that hot spots of LOH were more likely to correspond to a region localized telomeric to the gene. Therefore, these data suggest that other target genes for genetic inactivation exist in the 11q23 region.

Alleles↗

PubMed2003

Variants of developmental genes (TGFA, TGFB3, and MSX1) and their associations with orofacial clefts: a case-parent triad analysis.

We selected 262 case-parent triads from a population-based study of orofacial clefts in Norway, and examined variants of developmental genes TGFA, TGFB3, and MSX1 in the etiology of orofacial clefts. One hundred seventy-four triads of cleft lip cases (CL+/-P) and 88 triads of cleft palate only cases (CPO) were analyzed. There was little evidence for an association of any of these genes with CL+/-P. The strongest association was a 1.7-fold risk with two copies of the TGFB3-CA variant (95% CI=0.9-3.0). Among CPO cases, there was a 3-fold risk with two copies of the TGFA TaqI A2 allele, and no increase with one copy. Assuming this to be a recessive effect, we estimated a 3.2-fold risk among babies homozygous for the variant (95% CI=1.1-9.2). Furthermore, there was strong evidence of gene-gene interaction. While there was only a weak association of the MSX1-CA variant with CPO, the risk was 9.7-fold (95% CI=2.9-32) among children homozygous for both the MSX1-CA A4 allele and the TGFA A2 allele. No association of CPO with the TGFA variant was seen among the other MSX1-CA genotypes. In conclusion, no strong associations were found between CL+/-P and variants at these three genes. There was a possible recessive effect of the TGFA TaqI variant on the risk of CPO, with a 3-fold risk among children homozygous for the variant. The effect of this TGFA genotype was even stronger among children homozygous for the MSX1-CA A4 allele, raising the possibility of interaction between these two genes.

Adult↗

PubMed1993

Genetic diversity from a limited repertoire of mutations on different common allelic backgrounds: alpha 1-antitrypsin deficiency variant Pduarte.

alpha 1-Antitrypsin (alpha 1AT) is one of the most polymorphic gene loci in the human genome. alpha 1AT variants are typically identified by their migration position in an isoelectric focusing gel at pH 4-5. Heterogeneity of the isoelectric point of alpha 1AT variants, hence variant migration, most often results from amino acid substitutions which alter the net charge of the molecule. We identified an individual heterozygous for an alpha 1AT variant migrating in the "P" variant region which differs from other known "P" variants. Using isoelectric focusing on an immobilized pH gradient at pH 4.50-4.85 the novel P allele, Pduarte, migrates between Pst. albans and Plowell. Densitometric analysis of normal "M" type alpha 1AT and the deficiency variant Plowell major bands separated by isoelectric focusing demonstrates that Pduarte contributes approximately 41% as much alpha 1AT to the total serum alpha 1AT concentration as the normal "M" alpha 1AT, similar to Plowell. Direct DNA sequencing of the proband's genomic DNA demonstrates that the Pduarte allele differs from the normal M1 (V213) allele by two amino acid substitutions, R101 (CGT)-->H(CAT) and D256 (GAT)-->V(GTT). Individually, these amino acid substitutions characterize the normal M4 allele (R101-->H) and the deficient Plowell allele (D256-->V). Thus the Pduarte allele differs from the Plowell allele only by the normal allelic background in which the V256 mutation occurs. Comparison of amino acid sequences among several alpha 1AT variants demonstrates that Pduarte is an example of a more general observation regarding diversity within the PI (protease inhibitor) system.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed2006

DLG5 variants contribute to Crohn disease risk in a Canadian population.

Variants in the gene encoding the DLG5 scaffolding protein have been reported to be associated with increased risk of inflammatory bowel disease (IBD) and particularly Crohn's disease (Crohn disease; CD). These findings have not been uniformly replicated in follow-up studies. In this study we genotyped a cohort of 402 Canadian CD and 179 ulcerative colitis (UC) patients and 537 healthy controls for three IBD/CD-associated DLG5 variants. Our data reveal that the common DLG5 haplotype (A), which was previously considered protective for IBD, is associated with modest increases in risk for IBD (P=0.02) and CD (P=0.04). The effects of haplotype copy number on risk for IBD were minor, with the odds ratio (ORs) being 1.37 for the heterozygous risk genotype and 1.7 for the homozygous risk genotype. While we were unable to replicate the proposed association between the DLG5 c.113G>A variant and IBD, an association of IBD (P=0.02) and CD (P=0.04) with the rarer c.4136C>A variant was replicated in this cohort. These associations were restricted to the non-Jewish subjects in this cohort and were not detected in the Ashkenazi Jewish population studied here. Within the non-Jewish group, no associations were detected between the DLG5 variants and specific phenotypic features, such as site of disease, and there was no evidence of epistasis between DLG5 and any of the CD-associated CARD15 or SLC22A4/A5 gene variants. Together, the results indicate a role for DLG5 variants in IBD susceptibility and suggest that further studies are warranted to evaluate this role in different IBD populations and to determine the functional pathways that couple DLG5 variants to IBD.

Adult↗

PubMed2006

Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.

The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.

Adolescent↗

PubMed2002

Expression of MUC1 splice variants in benign and malignant ovarian tumours.

MUC1 is expressed on the surface of ovarian cancer cells. Nine different splice variants of MUC1 have been described, but no study has reported on the expression of MUC1 isoforms in human ovarian cancer. Our study compares patterns of expression of MUC1 splice variants of malignant and benign ovarian tumours. Ovarian tissue samples were taken from patients with benign ovarian tumours (n = 34) and from patients who had surgery for primary (n = 47) or recurrent (n = 8) ovarian cancer. RT-PCR for MUC1 splice variants A, B, C, D, X, Y, Z, REP and SEC was performed and their expression compared to clinical and histopathologic parameters. Variants A, D, X, Y and Z were more frequently expressed in malignant than in benign tumours. All primary ovarian cancer cases were positive for variant REP but negative for variant SEC. No significant association of the expression of MUC1 splice variants with the response to chemotherapy or patient survival could be demonstrated. Expression of MUC1 splice variants A, D, X, Y, Z and REP is associated with the presence of malignancy, whereas expression of MUC1/SEC is associated with the absence of malignancy.

Alternative Splicing↗

PubMed2005

Normalization of relative peptide ratios derived from in-gel digests: applications to protein variant analysis at the peptide level.

The ability to detect protein variants and post-translational modifications by mass spectrometry has become increasingly important. Unfortunately, the ability to detect variants in large intact proteins (>80,000 Da) is limited. Even in the analysis of smaller proteins, algorithms are required to determine the presence of a 2 Da mass shift in an intact 13 kDa protein because the isotopic distribution of the multiply charged ions of the variant overlaps the wild-type distribution. Fortunately, most modern instruments are capable of detecting variants in tryptic peptides derived from intact proteins. If a single common variant protein is known, the presence of a variant tryptic peptide can be easily demonstrated. A more difficult issue is the case where a multiplicity of peptides with multiple amino acid substitutions can be associated with pathology. In these cases a decrease in the relative amount of a variant peptide relative to other internal tryptic fragments would be diagnostic. However, the variability associated with the analysis of in-gel or solution digests of proteins, related to efficiencies in digestion, extraction and ionization, confounds variant analysis at the peptide level. A strategy was developed to normalize for this variability by utilizing multiple isotopically labeled internal standards for multiple peptides derived from the same protein. Erythrocyte spectrin from 36 normal and 25 abnormal osmotic fragility samples was analyzed as a test case. Three isotopically labeled target peptides comprising the alpha/beta-spectrin self-association sites were added to purified digested alpha-spectrin. The utilization of multiple internal standards demonstrates the capability to normalize for sample variability due to ionization efficiency, solvent effects, digestion and extraction efficiency.

Algorithms↗

PubMed1999

Lactation-dependent expression of an mRNA splice variant with an exon for a multiply O-glycosylated domain of mouse milk fat globule glycoprotein MFG-E8.

Expression of mRNA encoding MFG-E8, a milk fat-associated glycoprotein was investigated in mouse mammary gland. Two forms of mRNA, long and short variants, were shown to be expressed in the mammary tissue by RT-PCR analysis. Sequence analyses of these two variants and an isolated MFG-E8 gene segment indicated that the long and short mRNA variants resulted from an alternative splicing of a single pre-mRNA through in-flame inclusion and skipping of one exon, which encodes a proline/threonine (Pro/Thr)-rich domain. The long variant was expressed predominantly in mammary gland and the expression level was remarkably increased at late gestation and kept high during lactation. On the contrary, the short variant was detected ubiquitously in various tissues and its expression in the mammary gland was rather decreased in a lactation dependent manner. Expression of the long variant was also detected in a mouse mammary epithelial cell line, COMMA-1D, and enhanced by incubation with lactogenic hormones. Glycosylation inhibition analyses using tunicamycin and alpha-benzyl-GalNAc were conducted with COS7 cells transfected with plasmids expressing each mRNA variant, demonstrating that a fully glycosylated product of the long mRNA variant was not only N-glycosylated but also multiply O-glycosylated, whereas a product of the short one had only N-glycan(s). These results suggest that the alternative splicing plays a critical role for the mammary-specific and lactation-dependent expression of the MFG-E8 isoform and that the multiply O-glycosylated Pro/Thr-rich domain of this isoform is functionally important for formation of milk fat globules in mammary epithelial cells.

Alternative Splicing↗