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At least 343 records · Page 19Linked to original sources
PubMed2006

The p22phox C242T gene polymorphism is associated with a reduced risk of angiographically verified coronary artery disease in a high-risk Finnish Caucasian population. The Finnish Cardiovascular Study.

BACKGROUND: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a major source of the superoxide anion, which may play an important role in the development of atherosclerosis and coronary artery disease (CAD). The p22phox, a component of the NADPH oxidase, is essential for the activation of this enzyme, and intensive expression of the p22phox has been reported in human atherosclerotic arteries. However, studies on the association of the C242T polymorphism in the p22phox gene with CAD have produced conflicting results, and the relation of this polymorphism with CAD is not well known in a population with acquired risk factors enhancing the NADPH-dependent superoxide production. METHODS: As part of the Finnish Cardiovascular Study, a case-control study was conducted with 402 high-risk Finnish Caucasian patients undergoing coronary angiography. Genotyping was performed using the 5' nuclease TaqMan assay. RESULTS: The prevalence of the T allele (TT + TC genotypes) was significantly lower among angiographically verified CAD patients (n = 250) than among control subjects (n = 152, P = .013). In contrast to subjects with the CC genotype, the T allele was found protective against CAD (odds ratio = 0.531, 95% CI 0.331-0.852, P = .009), and the results remained significant after adjustment for other significant coronary risk factors. CONCLUSIONS: The T allele in the C242Tpolymorphism of the p22phox gene had a protective effect against the development of CAD despite the exposure of study subjects to risk factors related to excessive NADPH-dependent superoxide production.

Adult↗
PubMed2001

Prefrontal neurons and the genetics of schizophrenia.

This article reviews prefrontal cortical biology as it relates to pathophysiology and genetic risk for schizophrenia. Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. Abnormalities of prefrontal information processing also are found in unaffected individuals who are genetically at risk for schizophrenia, suggesting that genetic polymorphisms affecting prefrontal function may be susceptibility alleles for schizophrenia. One such candidate is a functional polymorphism in the catechol-o-methyl transferase (COMT) gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. The COMT genotype predicts performance on prefrontal executive cognition and working memory tasks. Functional magnetic resonance imaging confirms that COMT genotype affects prefrontal physiology during working memory. Family-based association studies have revealed excessive transmission to schizophrenic offspring of the allele (val) related to poorer prefrontal function. These various data provide convergent evidence that the COMT val allele increases risk for schizophrenia by virtue of its effect on dopamine-mediated prefrontal information processing-the first plausible mechanism for a genetic effect on normal human cognition and risk for mental illness.

Alleles↗
PubMed2003

Virological efficacy in HIV-infected patients affected by non-Hodgkin lymphoma, treated with antiblastic chemotherapy and highly active antiretroviral therapy.

This study evaluated replication of human immunodeficiency virus (HIV) and the genotypic resistance pattern in 26 HIV-infected patients affected by non-Hodgkin lymphoma who were treated with at least 3 cycles of chemotherapy (CT; rituximab and CDE) and highly active antiretroviral therapy (HAART). Genotyping was performed at baseline and when virological failure occurred. Six patients met the virological failure criteria. The genotyping analysis demonstrated that during CT administration new mutations might occur, but no significant changes in the pre-existing resistance patterns were observed. The data show that a combination therapy consisting of CT and HAART is feasible and that the virological response can be maintained in the majority of such patients.

Adult↗
PubMed2003

Phenotypic and genotypic differentiation of Campylobacter spp. isolated from Austrian broiler farms: a comparison.

An identification scheme based on restriction fragment length polymorphism of polymerase chain reaction products (PCR-RFLP) was developed to differentiate isolates of the genera Campylobacter, Arcobacter and Helicobacter. Based on the 16S rRNA gene of these genera, PCR amplified a 1216-bp fragment. The amplicons were digested with the restriction enzymes RsaI and EcoRV. Additional differentiation was obtained using a PCR-assay based on the hippuricase gene. Genotyping was performed on several reference strains from the National Collection of Typing Culture (NCTC), London, and on 130 field isolates. In parallel, a phenotypic differentiation was performed, in order to compare the results. In 119 cases (91.5%) the results obtained from the genotypic characterization were concordant with those from phenotypic testing. Co-infections with Campylobacter jejuni and Campylobacter coli in two samples and seven hippurate-negative C. jejuni-strains were identified by the genotypic method. Furthermore, PCR-RFLP assays identified an atypical isolate as Campylobacter fetus/hyointestinalis.

Animals↗
PubMed2005

Genomewide significant linkage to stuttering on chromosome 12.

Stuttering is a common and sometimes severe communication disorder, of unknown primary etiology, that exists in populations worldwide. Many types of evidence suggest a genetic contribution to stuttering; however, the complex inheritance of this disorder has hindered identification of these factors. We have employed highly inbred families to increase the power of linkage analysis of this disorder. Forty-four Pakistani families with documented or probable consanguinity, from the city of Lahore and surrounding areas, were included. Each family contained multiple cases of stuttering, which were diagnosed using the Stuttering Severity Instrument. Using the Marshfield Weber 9 marker panel, we performed a genomewide linkage scan focused on affected individuals and their parents. The analysis included 199 genotyped individuals, 144 affected and 55 unaffected. The Pedigree Relationship Statistical Test (PREST) was used to identify pedigrees that required additional specification of inbreeding. Initial nonparametric analysis gave evidence of linkage on chromosomes 1, 5, 7, and 12. Additional genotyping was performed on chromosome 12 to a 5-cM level of resolution, and 16 additional individuals were then included, bringing the number of families to 46. Analysis of the enlarged data set provided consistent evidence of linkage on chromosome 12: the S(homoz) scoring function gave a nonparametric LOD score of 4.61, and a LOD score of 3.51 was obtained using the S(all) scoring function. These results suggest that a locus on chromosome 12q may contain a gene with a large effect in this sample.

Chromosome Mapping↗
PubMed2001

Apolipoprotein E polymorphism and response to electroconvulsive therapy.

The aim of this study was to determine whether the apolipoprotein E genotype differs in patients who respond or do not respond to electroconvulsive therapy (ECT). Inpatients, out-patients, and day-treatment patients who had received ECT comprised the study group. The 34 patients included met DSM-III-R criteria for affective or schizoaffective disorder. Responder or nonresponder status was assessed using the Clinical Global Inventory and Montgomery Asberg Depression Rating Scale. Blood samples were taken and coded when the patients entered the study. DNA extraction and apolipoprotein E genotyping were performed with no knowledge of the clinical classification of the patients. A significant difference in E4 genotype distribution was found between ECT responders and nonresponders (p < 0.02); psychosis was significantly less frequent in this group (p = 0.046), and there was a trend toward older onset of depression among these persons (p = 0.10). Only the E3/3 genotype was found in the patients with early-onset depression. The E4 genotype appears to define a subgroup of patients with late-onset depression who respond to ECT. If confirmed in prospective studies, this may provide a useful marker in the treatment decision-making process for late-onset depression.

Adolescent↗
PubMed2007

Apolipoprotein E genotype affects the response to lipid-lowering therapy in Chinese patients with type 2 diabetes mellitus.

OBJECTIVE: To evaluate the effect of apolipoprotein E (apoE) genotype on baseline lipid levels and the response to hydroxy-methyl glutaryl coenzyme A reductase inhibitors (statins) therapy in Chinese patients with type 2 diabetes mellitus (DM). RESEARCH DESIGN AND METHODS: We consecutively recruited Chinese patients with type 2 DM requiring lipid-lowering therapy according to current guidelines. Patients were started on either simvastatin 10 mg daily or given an equivalent dose of lovastatin 20 mg. After 12 weeks of statin therapy, patients had fasting lipid profiles repeated. ApoE genotyping was performed by restriction fragment length polymorphism (RFLP). RESULTS: Ninety-six patients were studied. The epsilon3/epsilon3 genotype was in 62.5%, epsilon2/epsilon3 and epsilon3/epsilon4, 16.7 and 20.8%, respectively. After adjusting for confounding variables, baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly higher in those with epsilon3/epsilon4 compared with epsilon2/epsilon3 genotype (6.7 vs. 5.5 mm for TC, 4.5 vs. 3.6 mm for LDL-C; p = 0.015 and p = 0.025, respectively). With statin therapy, epsilon3/epsilon4 patients had significantly greater LDL-C lowering compared with epsilon2/epsilon3 patients (48 vs. 27.7%; p = 0.04). There was no gender difference in baseline lipid parameters or response to statin therapy. CONCLUSIONS: ApoE genotype accounts for interindividual variability of baseline cholesterol levels, and response to statin therapy in Chinese patients with type 2 DM.

Apolipoproteins E↗
PubMed2005

Gene polymorphisms of angiotensin II type 1 receptor and angiotensin-converting enzyme in two ethnic groups living in Zhejiang Province, China.

Polymorphisms of ACE insertion/deletion (I/D) and angiotensin II type 1 receptor (AT1R) 1166A-C have been associated with many diseases, and distributions of their genotypes vary in different races and populations. The aim of this study was to investigate distributions of angiotensin-converting enzyme (ACE) and AT1R genotypes in Han and She populations in ZheJiang province. We determined ACE and AT1R genotypes in 189 Han and 163 She individuals. DNA was extracted from peripheral blood samples. Analyses of ACE and AT1R genotypes were performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The frequencies of ACE genotypes and alleles among the Han sample (41.3%II, 41.3%ID, 17.5%DD; 61.9%I allele, 38.1%D allele) were similar to those among She individuals (39.9%II, 39.3%ID, 20.9%DD; 59.5%I allele, 40.5%D allele), with p=0.660; p=0.421. However, significant differences in the distributions of ACE polymorphism between men and women among She population were observed, with p=0.042, p=0.014. AT1R genotype and allele frequencies in the Han population were (88.4%AA, 11.1%AC, 0.5%CC) and (93.9%A allele, 6.1%C) allele respectively. In the She population they were (78.0%AA, 21.3%AC, 0.6%CC) and (89.0%A allele, 11.0%C allele). The significant differences were found between Han and She populations with p=0.031, p=0.018, and within subgroups of women, with p=0.010, p=0.021. There were no significant differences within subgroups of men (p=0.476, p=0.261). The genotype distributions or allele frequencies of ACE and AT1R were significantly different between the samples of the She and Han populations.

Asian People↗
PubMed2004

GSTT1, GSTM1 and CYP2E1 genetic polymorphisms in gastric cancer and chronic gastritis in a Brazilian population.

AIM: To test the hypothesis that, in the Southeastern Brazilian population, the GSTT1, GSTM1 and CYP2E1 polymorphisms and putative risk factors are associated with an increased risk for gastric cancer. METHODS: We conducted a study on 100 cases of gastric cancer (GC), 100 cases of chronic gastritis (CG), and 150 controls (C). Deletion of the GSTT1 and GSTM1 genes was assessed by multiplex PCR. CYP2E1/PstI genotyping was performed using a PCR-RFLP assay. RESULTS: No relationship between GSTT1/GSTM1 deletion and the c1/c2 genotype of CYP2E1 was observed among the three groups. However, a significant difference between CG and C was observed, due to a greater number of GSTT1/GSTM1 positive genotypes in the CG group. The GSTT1 null genotype occurred more frequently in Negroid subjects, and the GSTM1 null genotype in Caucasians, while the GSTM1 positive genotype was observed mainly in individuals with chronic gastritis infected with H pylori. CONCLUSION: Our findings indicate that there is no obvious relationship between the GSTT1, GSTM1 and CYP2E1 polymorphisms and gastric cancer.

Adolescent↗
PubMed1998

[Lack of relationship between angiotensinogen gene m235t polymorphism and gene insertion/deletion (I/D-intron 16) and Pst I RFLP (P/M-intron 7) polymorphisms of the angiotensin I converting enzyme(ACE) gene and the development of H-gestosis. Preliminary results].

Genetic and familial factors may predispose to H-gestosis. The aim of our study was to answer the question if angiotensinogen gene m235t polymorphism, and ACE gene I/D and Pst I RFLP polymorphisms may be markers of genetic predisposition to the H-gestosis. 246 pregnant women (median age 26 years) were studied (the studied group consisted of 116 women with H-gestosis and the control group consisted of 130 healthy pregnant women). Genotyping was performed using polymerase chain reaction method. Statistical analysis was done by means of Statistica for Windows. Genotype distribution was analyzed using chi 2 test. P < 0.05 was considered as statistically significant. In our study we did not receive statistically significant differences in ACE and angiotensinogen genes genotype distributions and allele frequencies between the investigated groups. Based on results of the study we may suggest that I/D and Pst I RFLP ACE gene polymorphism and angiotensinogen gene m235t polymorphism do not play any significant role in the pathogenesis of H-gestosis.

Adolescent↗
PubMed2006

Prediction of Alzheimer's disease in mild cognitive impairment: a prospective study in Taiwan.

The relationship between apolipoprotein E (ApoE) and clinical manifestations of mild cognitive impairment (MCI) has not been investigated in non-Caucasian populations. This prospective study was conducted in an ethnic Chinese population to evaluate the correlations of ApoE genotype, cognitive performance, medial temporal structure volumes, and clinical outcome in amnestic MCI. Twenty normal elders, 58 MCI, and 20 mild Alzheimer's disease (AD) patients received neuropsychological, MRI, and ApoE genotype assessments at baseline. Patients with MCI had intermediate cognitive performance and hippocampal volumes between those in normal and AD groups. In each diagnostic group, epsilon4 carriers (E4+) consistently had smaller hippocampal volume than non-carriers (E4-) did. Nineteen MCI subjects (32.7%) converted to AD during the 3-year study period. Compared with MCI non-converters and E4- MCI converters, E4+ MCI converters had the smallest hippocampal volume. However, epsilon4 was not a predictor for AD. Both cognitive performance and hippocampal volume were predictive for progression to AD. However, stepwise Cox regression model integrating both neuropsychological and radiological variables showed that global cognitive performance was the only significant predictor for AD. A poor global cognitive score may be more crucial than a small hippocampal volume in the prediction of AD.

Aged↗
PubMed2006

The MCI study in Taiwan.

Veterans General Hospital started study for mild cognitive impairment (MCI) since 1996. We used clinical dementia rating (CDR) of 0.5 to define our questionable dementia (QD) subjects. These QD subjects received annual neuropsychological assessment in 5-year follow-up period. Annual conversion rate, apolipoprotein E (ApoE) genotype and neuropsychological risk factors for QD were investigated. We found a 19.9% person-year conversion rate for these QD subjects. Both of the poor cognitive performance and ApoE epsilon4 allele were risk factors for progressing to dementia. Based on the results of this study and the progress in the concept of MCI, we added more complex verbal and visual memory tests as well as MRI-based volumetry measurement in our subsequent research. Peterson's amnestic MCI criteria were used to diagnose our MCI subjects. In the 3-year follow-up period, the conversional rate was 18.2% person-year for MCI subjects, similar to our previous finding in QD. We found hippocampal volume was positively associated with cognitive performance. ApoE genotype had effect on hippocampal volume. Subjects with lower cognitive performance and smaller hippocampi had higher risk converting to AD. With rapidly expanding research on dementia and MCI worldwide, we are looking forward to seeing the integration in neurobiology, neuroimaging, and neurobehavior fields to establish a multidisciplinary approach to MCI and dementia.

Alzheimer Disease↗
PubMed2006

Influence of genotype and diet on steer performance, manure odor, and carriage of pathogenic and other fecal bacteria. II. Pathogenic and other fecal bacteria.

This study assessed the influence of cattle genotype and diet on the carriage and shedding of zoonotic bacterial pathogens and levels of generic Escherichia coli in feces and ruminal contents of beef cattle during the growing and finishing periods. Fifty-one steers of varying proportions of Brahman and MARC III [0 (15), 1/4 (20), 1/2 (7), and 3/4 Brahman (9)] genotypes were divided among 8 pens, such that each breed type was represented in each pen. Four pens each were assigned to 1 of 2 diets [100% chopped bromegrass hay or a diet composed primarily of corn silage (87%)] that were individually fed for a 119-d growing period, at which time the steers were switched to the same high-concentrate, corn-based finishing diet and fed to a target weight of 560 kg. Feces or ruminal fluid were collected and analyzed at alternating intervals of 14 d or less. Generic E. coli concentrations in feces or ruminal fluid did not differ (P > 0.10) by genotype or by growing diet in the growing or finishing periods. However, the concentrations in both feces and ruminal fluid increased in all cattle when switched to the same high-corn diet in the finishing period. There was no effect (P > 0.25) of diet or genotype during either period on E. coli O157 shedding in feces. Forty-one percent of the steers were positive for Campylobacter spp. at least once during the study, and repeated isolations of Campylobacter spp. from the same steer were common. These repeated isolations from the same animals may be responsible for the apparent diet (P = 0.05) and genotype effects (P = 0.02) on Campylobacter in feces in the finishing period. Cells bearing stx genes were detected frequently in both feces (22.5%) and ruminal fluid (19.6%). The number of stx-positive fecal samples was greater (P < 0.05) for 1/2 Brahman steers (42.9%) than for 1/4 Brahman (25.0%) or 3/4 Brahman steers (22.2%), but were not different compared with MARC III steers (38.3%). The greater feed consumption of 1/2 Brahman and MARC III steers may have resulted in greater starch passage into the colon, accompanied by an increase in fecal bacterial populations, which may have further improved the ability to detect stx genes in these cattle. There was no correlation between either ADG or daily DMI and the number of positive samples of E. coli O157, Campylobacter spp., or stx genes, which agrees with our current understanding that these microorganisms occur commonly in, and with no measurable detriment to, healthy cattle.

Animal Feed↗
PubMed2003

High accuracy genotyping directly from genomic DNA using a rolling circle amplification based assay.

BACKGROUND: Rolling circle amplification of ligated probes is a simple and sensitive means for genotyping directly from genomic DNA. SNPs and mutations are interrogated with open circle probes (OCP) that can be circularized by DNA ligase when the probe matches the genotype. An amplified detection signal is generated by exponential rolling circle amplification (ERCA) of the circularized probe. The low cost and scalability of ligation/ERCA genotyping makes it ideally suited for automated, high throughput methods. RESULTS: A retrospective study using human genomic DNA samples of known genotype was performed for four different clinically relevant mutations: Factor V Leiden, Factor II prothrombin, and two hemochromatosis mutations, C282Y and H63D. Greater than 99% accuracy was obtained genotyping genomic DNA samples from hundreds of different individuals. The combined process of ligation/ERCA was performed in a single tube and produced fluorescent signal directly from genomic DNA in less than an hour. In each assay, the probes for both normal and mutant alleles were combined in a single reaction. Multiple ERCA primers combined with a quenched-peptide nucleic acid (Q-PNA) fluorescent detection system greatly accellerated the appearance of signal. Probes designed with hairpin structures reduced misamplification. Genotyping accuracy was identical from either purified genomic DNA or genomic DNA generated using whole genome amplification (WGA). Fluorescent signal output was measured in real time and as an end point. CONCLUSIONS: Combining the optimal elements for ligation/ERCA genotyping has resulted in a highly accurate single tube assay for genotyping directly from genomic DNA samples. Accuracy exceeded 99 % for four probe sets targeting clinically relevant mutations. No genotypes were called incorrectly using either genomic DNA or whole genome amplified sample.

Chromosomes, Human, Pair 6↗
PubMedDate not supplied

Use of bDNA testing in the immunologically nonresponding patient who has a low or undetectable viral load by RT-PCR testing.

BACKGROUND: Studies have shown that reverse transcription-polymerase chain reaction (RT-PCR) technology underquantifies viral loads in patients with non-B clades of HIV-1. Testing with bDNA technology gave higher viral loads in these subtypes. A study was conducted to determine whether virologically responding patients on HAART who were not immunologically responding would have higher viral loads using bDNA technology and whether these differences were due to non-B clades. METHOD: Forty-eight patients receiving HAART for more than 6 months who were having inappropriate immunologic responses in spite of undetectable or very low viral loads determined by RT-PCR (<3000 copies by Roche Amplicor 1.0) were studied. These patients had bDNA viral loads performed. All patients who had bDNA viral loads equivalent to >3000 by RT-PCR had clade and genotypic studies performed. RESULTS: Fifteen patients had viral loads by bDNA that were equivalent to >3000 copies by RT-PCR. Four of these were found to have non-B clades (one D clade and three AG clade). The D clade patient had multidrug resistance; none of the AG clade patients had resistance. Of the remaining 11 patients, virus could not be recovered from 2 and 9 had a B clade. Six of these nine had genotypic resistance to HAART drugs. CONCLUSION: bDNA testing may be useful in the immunologically nonresponding patient.

Adult↗
PubMed2006

Vascular endothelial growth factor polymorphisms in gastric cancer development, prognosis, and survival.

BACKGROUND: Angiogenesis plays an important role in growth, progression, and metastasis of tumors. Vascular endothelial growth factor (VEGF) overexpression has been associated with advanced stage and poor survival in several cancers. METHODS: The association of functional single nucleotide polymorphisms (SNPs) of VEGF gene with gastric cancer development, prognosis, and survival in a case-control study of 100 gastric cancer Greek patients was evaluated. The genotyping was performed by PCR-RFLP analysis. RESULTS: Our results revealed a marginally significant association of the 634CC genotype (P = 0.042) with increased risk for gastric cancer development. None of the rest of the examined polymorphisms or haplotypes conferred any gastric cancer susceptibility. A strong association between the -2578AA (P = 0.025), -634CC (P = 0.013), +936CT (P = 0.028), +936TT (P = 0.0001) genotypes and a larger tumor size was observed, while the 2578AA and -634CC genotypes were strongly correlated to poor differentiation (P = 0.01) and advanced stage of disease (P = 0.039), respectively. In addition, our results indicated that metastatic disease frequency was more accentuated among the +936TT carriers (P = 0.0035). Interestingly, carrying the -634CC genotype was associated with decreased overall survival rates (46.67%). CONCLUSIONS: The present study suggests that VEGF polymorphisms may contribute to gastric tumor characteristics; these observations, however, requiring further confirmation in a larger multi-ethnic study.

Aged↗
PubMed2007

Manganese superoxide dismutase polymorphism and risk of skin cancer (United States).

OBJECTIVE: We assessed whether the functional V16A polymorphism in the MnSOD gene is associated with skin cancer risk. METHODS: We conducted a nested case-control study (219 melanoma, 286 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 873 matched controls) within the Nurses' Health Study. Genotyping was performed by the 5' nuclease assay (TaqMan). We used logistic regression to model the association between the genotype and skin cancer risk. RESULTS AND CONCLUSIONS: Overall, there was no significant association between this polymorphism and the risk of each type of skin cancer. No significant interaction was observed between this polymorphism and sunburn history and constitutional susceptibility on skin cancer risk. For interactions between intakes of alpha-carotene and beta-carotene and the MnSOD polymorphism on SCC, the inverse association of intake of either carotene with SCC risk was limited to the Val carriers, whereas no association was observed among women with the AA genotype. We observed an interaction between total vitamin C intake and the MnSOD polymorphism on melanoma risk. No interaction was observed for the intakes of other carotenoids, vitamin E, and vitamin A. Further research is needed to confirm these possible associations.

Adult↗
PubMed2025

DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting &#x3b1; helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.

Adolescent↗