Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients.
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Attention Deficit Disorder with Hyperactivity↗
Biomedical subjects
S S Sommer
Publications and source records attributed to S S Sommer.
The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study.
While Factor V (FV) Leiden is a risk factor for venous thromboembolism (VTE), the incidence of VTE among FV Leiden carriers is uncertain. The objective of the study was to estimate the overall age-specific and pregnancy-related VTE incidence and the relative risk among FV Leiden carriers. In a community-based sample of 3424 south-eastern Minnesota residents, 230 (6.7%) were genotyped as FV Leiden carriers; 220 carriers (mean age = 68 years) could be matched to a non-carrier on age, gender, ethnicity and length of medical history. We performed a retrospective cohort study of carriers and non-carriers by reviewing the complete medical records in the community for demographic and baseline characteristics, pregnancies and live births, and first lifetime VTE. Over 14 722 person-years, 24 (10.9%) carriers developed VTE [overall incidence = 163 (95% CI 104, 242) per 100,000 person-years]. VTE incidence rates for ages 15-29, 30-44, 45-59 and > or = 60 years were 0, 61, 244 and 764 per 100,000 person-years, respectively (cumulative VTE incidence at age 65 years = 6.3%). VTE incidence for carriers did not differ significantly from that for non-carriers except for those > or = 60 years old (relative risk = 3.6; 95% CI 2.0, 6.0). There were 311 live births among 130 women carriers; no VTE events occurred during pregnancy or postpartum [incidence = 0 (95% CI 0, 1186) per 100,000 women-years]. Most FV Leiden carriers do not develop VTE. Among all carriers, those > or = 60 years old are at the highest risk for VTE. The incidence of VTE among asymptomatic women carriers during pregnancy is low and insufficient to warrant prophylaxis.
Age Factors↗
Microdissection and molecular analysis of single cells or small cell clusters in pathology and diagnosis--significance and challenges.
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Cytological Techniques↗
Human germline mutation in the factor IX gene.
The molecular epidemiology of factor IX germline mutations in patients with hemophilia B has been studied in detail because it is an advantageous model for analyzing recent germline mutations in humans. It is estimated that mutations have been defined in the majority of nucleotides that are the target for mutation. The likelihood that a factor IX missense mutation will cause disease correlates with the degree of evolutionary conservation of the amino acid. Mutation rates per base-pair have been estimated after careful consideration and correction for biases, predicting about 76 de novo mutations per generation per individual resulting in 0.3 deleterious changes. The male-to-female sex ratio of mutation varies with the type of mutation. There is evidence for a maternal age effect and an excess of non-CpG G:C to A:T transitions. The factor IX mutation pattern is similar among geographically, racially and ethnically diverse human populations. The data support primarily endogenous mechanisms of germline mutation in the factor IX gene. Mutations at splice junctions are compatible with simple rules for predicting disease causing mutations.
Age Factors↗
Diagnosis of Duchenne dystrophy by enhanced detection of small mutations.
OBJECTIVE: To determine whether detection of small mutations of the dystrophin gene can be increased using an enhanced method of single-strand conformation polymorphism analysis. BACKGROUND: Usual methods of DNA analysis for Duchenne dystrophy cannot identify mutations in one-third of cases. Muscle biopsy, with its inherent risks and added liability for patients with Duchenne dystrophy, becomes the sole method of diagnosis. Even with a tissue diagnosis of dystrophin deficiency, many families are excluded from carrier detection and prenatal diagnosis. METHODS: Genomic DNA from a cohort of 93 patients with Duchenne dystrophy without identifiable gene mutations was screened for mutations. In each case, 22 kilobases of genomic DNA were scanned, including all 79 exons of the dystrophin gene, adjacent intronic regions, and six alternative exons 1. RESULTS: Sixty-eight (73%) had small mutations, including 34 nonsense mutations, 27 microdeletions and insertions, and 7 splice site mutations. No missense mutations were found. One nonsense mutation in exon 59 was detected in four patients. Most mutations were new; 54 of 62 different small mutations have not been reported. Mutations were found throughout the gene: 24% in the first quartile, 31% in the second, 16% in the third, and 29% in the fourth. CONCLUSIONS: A highly sensitive single-strand conformation polymorphism method substantially increased detection of small dystrophin gene mutations and made it possible to diagnose approximately 90% of patients with Duchenne dystrophy by DNA analysis. These findings, combined with cost savings and safety issues, provide compelling reasons to consider DNA analysis as the initial diagnostic test for the suspected dystrophin-deficient patient.
Adolescent↗
Scanning of estrogen receptor alpha (ERalpha) and thyroid hormone receptor alpha (TRalpha) genes in patients with psychiatric diseases: four missense mutations identified in ERalpha gene.
Estrogen and thyroid hormones exert effects on growth, development, and differentiation of the nervous system. Hormone administration can lead to changes in behavior, suggesting that genetic variants of the estrogen receptor alpha (ERalpha) and the thyroid hormone receptor alpha (TRalpha) genes may predispose to psychiatric diseases. To investigate this possibility, regions of likely functional significance (all coding exons and flanking splice junctions) of the ERalpha and TRalpha genes were scanned in patients with schizophrenia (113), along with pilot studies in patients with bipolar illness (BPI), puerperal psychosis, autism, attention-deficit hyperactivity disorder (ADHD), and alcoholism. A total of 1.18 megabases of the ERalpha gene and 1.16 megabases of the TRalpha gene were scanned with Detection of Virtually All Mutations-SSCP (DOVAM-S), a method that detects virtually all mutations. Four missense mutations, seven silent mutations and one deletion were identified in the ERalpha gene, while only four silent mutations were present in the TRalpha gene. Two of the missense mutations in ERalpha are conserved in the six available mammalian and bird species (H6Y, K299R) and a third sequence variant (P146Q) is conserved in mammals, birds, and Xenopus laevis, hinting that these sequence changes will be of functional significance. These changes were found in one patient each with BPI, puerperal psychosis, and alcoholism, respectively. Analysis of the ERalpha and TRalpha genes in 240 subjects reveals that missense changes and splice site variants are uncommon (1.7% and 0%, respectively). Further analyses are necessary to determine if the missense mutations identified in this study are associated with predisposition or outcome for either psychiatric or nonpsychiatric diseases.
Alleles↗
Mutation frequency is reduced in the cerebellum of Big Blue mice overexpressing a human wild type SOD1 gene.
Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by motor neuron degeneration. A similar disease phenotype is observed in mice overexpressing a mutant human hSOD1 gene (G93A, 1Gurd(1)). Mice transgenic for lacI (Big Blue) and human mutant (1Gurd(1), Mut hSOD1) or wild type (2Gur, Wt hSOD1) SOD1 genes were used to examine spontaneous mutation, oxidative DNA damage, and neurodegeneration in vivo. The frequency and pattern of spontaneous mutation were determined for forebrain (90% glia), cerebellum (90% neurons) and thymus from 5-month-old male mice. Mutation frequency is not elevated significantly and mutation pattern is unaltered in Mut hSOD1 mice compared to control mice. Mutation frequency is reduced significantly in the cerebellum of Wt hSOD1 mice (1.6x10(-5); P=0.0093; Fisher's Exact Test) compared to mice without a human transgene (2.7x10(-5)). Mutation pattern is unaltered. This first report of an endogenous factor that can reduce in vivo, the frequency of spontaneous mutation suggests potential strategies for lowering mutagenesis related to aging, neurodegeneration, and carcinogenesis.
Amyotrophic Lateral Sclerosis↗
Spontaneous microdeletions and microinsertions in a transgenic mouse mutation detection system: analysis of age, tissue, and sequence specificity.
A total of 3497 independent spontaneous mutations were examined using the Big Blue transgenic mouse mutation detection system. Base substitutions predominate, although 16% of somatic and germline mutations are microdeletions, microinsertions, or deletions combined with insertions. The pattern of microdeletions and microinsertions is similar in both the lacI transgene and the human p53 gene. Single-base deletions (D1) and insertions (I1) are evenly distributed in the lacI transgene, whereas microdeletions from 2 to 50 bp are clustered at two regions (bp 129-228 and 529-628). The pattern of microdeletions and microinsertions is similar between young (< or =3 months) and old (25 months) mice. Brain tissue has a paucity of deletions combined with insertions when compared with that of thymus and nine other tissues (P = 0.01). A 16-bp deletion at lacI base position 272 is a tissue-specific hotspot preferentially occurring in brain. Approximately 68 and 93% of D1 and I1, respectively, occur at mononucleotide repeats. The frequencies of D1 and I1 in mononucleotide repeats increase in an exponential manner with the length of the repeat. The lacI transgene shows similarity to the human p53 gene in the pattern of microdeletions and microinsertions and the size distribution of microdeletions.
Age Factors↗
Frequency of recent retrotransposition events in the human factor IX gene.
Two germline retrotransposition mutations of recent origin were observed in 727 independent mutations (0.28%) in the human factor IX gene (F9) of patients with hemophilia B: 1) a 279 bp insertion in exon H originating from an Alu family of short interspersed elements not previously known to be active and, 2) a 463 bp insertion in exon E of a LINE1 element originating in the maternal grandmother. If the rates of recent germline mutation in F9 are typical of the genome, a retrotransposition event is estimated to occur somewhere in the genome of about one in every 17 children born. Analysis of other estimates for retrotransposition frequency and overall mutation rates suggests that the actual rate of retrotransposition is likely to be in the range of one in every 2.4 to 28 live births.
Alu Elements↗
An in-frame deletion in the alpha(2C) adrenergic receptor is common in African--Americans.
alpha(2) adrenergic receptors are activated by adrenaline and noradrenaline, and three subtypes (ie, A, B, C) have differential affinities for antagonists and medications. The alpha(2c) adrenergic receptor (ADRA2C), located on chromosome 4p16.3, is a candidate gene for schizophrenia because it binds clozapine, an atypical neuroleptic useful for treatment-resistant schizophrenia. In addition, ADRA2C binds clonidine which is prescribed for three psychiatric diseases. This report communicates the findings of the genetic scanning of this gene of very tough GC content. The complete coding sequences and splice junctions were scanned with [DOVAM]-S in 104 schizophrenics, and pilot probes of patients with alcoholism (41 patients), cocaine abuse (25 patients), puerperal psychosis (30 patients), attention deficient/hyperactivity disorder (25 patients) and autism (25 patients). Six sequence variants were found, including five silent polymorphisms (allele frequencies 0.6--25%) and an in-frame deletion of a homologous repeat at nucleotides 967--978 (ie, TIDRU(1)). Genotyping of the normal two repeat unit of the Third Intracytoplasmic Domain Repeat Unit (TIDRU(2)) and the deleted variant (TIDRU(1)) revealed that TIDRU(1) had allelic frequencies of 39% (11/28) and 3.5% (6/172) in African-American and Caucasian schizophrenics, respectively, and it occurred with equal frequency in controls (44%, 31/70 and 3.0%, 6/198). TIDRU(1) occurs at a location similar to the third intracytoplasmic 48-nucleotide repeat unit in the DRD4 that is associated with ADHD. Although these data do not suggest an association of TIDRU(1) with schizophrenia, additional studies are needed to see whether TIDRU(1) confers a clinical phenotype.
Black People↗
Systematic screening for mutations in the glycine receptor alpha2 subunit gene (GLRA2) in patients with schizophrenia and other psychiatric diseases.
The glycine receptor, which is a member of the ligand-gated ion channel superfamily, mediates synaptic inhibition in the spinal cord and other brain regions. This superfamily has been implicated in the pathogenesis of schizophrenia and other psychiatric diseases. The complete coding sequence and splice junctions of the GLRA2 gene were scanned by DOVAM-S, a form of SSCP analysis with sufficient redundancy to detect virtually all mutations. Those analyses were performed in 113 patients with schizophrenia, and in pilot studies of patients with bipolar illness, alcoholism, puerperal psychosis, autism, and attention-deficit hyperactivity disorder (533 kb total scanned sequences). We detected three sequence changes in the coding region, all resulting in silent mutations: C894T in exon 5, C1134T in exon 7, and C1476T in exon 9. These do not alter the structure or the expression of the protein. It is unlikely that mutations in the coding region and splice junction of GLRA2 gene are associated with schizophrenia and other psychiatric diseases.
Alcoholism↗
High plating density improves Big Blue system efficiency without loss of sensitivity.
To increase efficiency in the Big Blue system, the plating density was increased from 15000 to 30000 or 45000 plaque forming units (pfus) per plate by increasing the density of the E. coli lawn and decreasing individual plaque size. Small plaque size ensured minimal overlap of the plaques. Liver from one 3- and one 25-month-old mouse (low and high mutation frequencies, respectively) was analyzed and neither plating density nor plaque size affected mutant/mutation frequency and pattern. The color intensity of particular mutant plaques was not affected by plaque size or plating density. Optimal sensitivity is achieved by sequencing mutants to calculate the mutation frequency from the mutant frequency and to identify altered patterns of mutation. Detailed effort and cost accounting of the Big Blue system (including mouse handling, DNA extraction, plaque screening, plaque purification, and DNA sequencing) reveals that one-quarter of the total effort is devoted to plating and screening of plates. This effort is reduced two fold with high plating density. The total cost of the Big Blue system is reduced by 17%. The total cost of the High Plating Density Big Blue system is now only 12% more costly than a selectable assay and offers an extensively validated system with a large mutation database representing a decade of effort.
Animals↗
Evidence that proximal multiple mutations in Big Blue transgenic mice are dependent events.
To characterize the nature of multiple mutations in the tissues of an intact animal, the Big Blue transgenic mouse mutation detection system was used to examine 1459 mutants from eight normal tissues and 507 mutants from 11 tumors. Multiple mutations occurred and predominantly doublet mutants were identified (i.e. two mutations within one mutant lacI gene), but multiplets of up to five mutations were observed. The frequency of doublets in normal tissues and spontaneous tumors from p53-deficient mice was enhanced to the same degree (660 and 667 fold, respectively) over that expected for two independent mutational events. Doublets, multiplets and singlets have similar patterns of mutation. The distance between mutations in doublets fits an exponential distribution, not that expected for randomly spaced events, suggesting that many doublets occur in rapid succession within the same cell cycle.
Animals↗
Five missense variants in the amino-terminal domain of the glucocorticoid receptor: no association with puerperal psychosis or schizophrenia.
Steroid hormone administration causes behavior changes in many and psychosis in a few. The clinical features suggest that genetic variants of the glucocorticoid receptor or cofactors could produce susceptible subpopulations who react adversely to hormonal cascades. To investigate this possibility, coding and splice site sequences of the glucocorticoid receptor were scanned for single nucleotide polymorphisms in genomic DNA samples from 100 schizophrenics (86 Caucasians and 14 African-Americans) and 40 Caucasians with puerperal psychosis. Five amino acid substitutions were found in the amino-terminal domain at frequencies of 0.6 to 3.8% in Caucasians: R23K, F29L, L112F, D233N, and N363S. In addition, four silent nucleotide changes were found: E22E, K293K, D677D, and N766N; a transversion in intron 4 occurred beyond the splice junction. None of these variants can be linked to these disorders at present. However, the N363S variant contributes a new potential phosphorylation site and has been associated with increased body mass and reduced bone mineral density [Huizenga et al., 1998], so it is possible that the other missense variants confer traits that currently are unrecognized. Comparisons to natural glucocorticoid receptor mutants in the familial glucocorticoid resistance syndrome and steroid resistant leukemias suggest that amino acid substitutions at highly conserved residues may cause severe functional defects and serious illness, while changes at less conserved sites produce lesser alterations and milder disease.
Amino Acid Sequence↗
Discrete mobility of single-stranded DNA in non-denaturing gel electrophoresis.
Gel electrophoresis is the standard method to separate, identify and purify nucleic acids. SSCP detects single base changes by altered mobility of single-stranded segments electrophoresed through non-denaturing polyacrylamide gels. Herein, changes in electrophoretic mobilities due to single base substitutions were measured for single-stranded segments of lengths ranging from 333 to 547 nt. A 484 nt segment in exon H of the human factor IX gene was studied most intensively. After SSCP, mobilities were determined by scanning autoradiograms at very high resolution (1200 d.p.i.), which allowed precise measurement of mobilities. When the mobilities of 46 single base substitutions were characterized, the distribution of mutant segments relative to a wild-type control was found to be discrete, i.e. the observed mobility values occurred in distinct ranges. Discrete mobility distributions were seen at different electrophoretic temperatures, buffer concentrations, segment lengths and segment sequences. In addition: (i) single base substitutions caused discontinuous distributions between highly dispersed and sharp bands; (ii) at least one single-stranded segment produced two sharp bands of similar intensity. These observations suggest that: (i) the single base changes in DNA segments in the size range 333-547 nt result in discrete conformational changes; (ii) individual DNA molecules of the same DNA segment can occasionally adopt two or more discrete conformations.
DNA, Single-Stranded↗
A prospective trial of midwest breast cancer patients: a p53 gene mutation is the most important predictor of adverse outcome.
Several retrospective studies have suggested p53 gene mutation as an adverse prognostic indicator in breast cancer patients, based on a selective growth advantage of p53 mutant cancer cells and their presumed resistance to current adjuvant therapy regimens. A cohort of 90 Caucasian midwestern breast cancer patients was analyzed prospectively (60 months of follow-up) with a rigorous mutation detection methodology. The presence of a p53 gene mutation was the single most adverse prognostic indicator for recurrence (p = 0.0032) and death (p = 0.0001), and was associated with poor response to both adjuvant (p = 0.0001) and palliative (p = 0.006) therapy. Analysis of the p53 gene with appropriate mutation detection methodology markedly improves the prediction of early recurrence, treatment failure, and death in breast cancer patients.
Breast Neoplasms↗
Nine independent F9 mutations in the Mexican hemophilia B population: nonrandom recurrences of point mutation events in the human germline.
The factor IX gene (F9) is a valuable model for studying germ-line mutations. Nine mutations were detected in nine Mexican patients with hemophilia B by direct sequencing using genomic amplification with transcript sequencing (GAWTS): six single base changes, one micro-deletion, and two large deletions. Germline origins of mutations were found in three of six families with sporadic cases. Curiously, the four independent single base substitutions which were not at CpG dinucleotides occurred at only two different nucleotide positions (17,678 and 17,747) one transition and one transversion at each. The two remaining substitutions were identical changes at a CpG dinucleotide, but were determined to be independent by germline origin analysis. A statistical analysis suggests that the independent recurrence of mutations at these locations may reflect an unusual aspect of F9 mutagenesis in the Mexican population. These data raise the possibility of population-specific differences in human germline mutations.
Factor IX↗
The human factor IX gene as germline mutagen test: samples from Mainland China have the putatively endogenous pattern of mutation.
Germline mutations are the major source of genetic variation that allows a species to evolve over time but at the cost of Mendelian disease and genetic predisposition to multifactorial diseases. Previous analyses have revealed that the pattern of germline mutations in the factor IX gene (F9) is similar among a variety of ethnically and geographically diverse populations and compatible with the ancient pattern that has shaped the mammalian genome. Here, we compare the pattern of germline mutation in a population of hemophilia B patients from Mainland China (n=66) to that in U.S. Caucasians, Blacks, and Mexican Hispanics and stratify by disease severity and ethnicity. The similar pattern of germline mutation in all ethnic groups studied to date provides additional data compatible with the inference that endogenous processes predominate in germline mutations.
China↗