Biomedical subjects
Publications and source records attributed to S N Thibodeau.
Approximately 700 hemoglobin variants have been reported, causing a variety of clinical manifestations, with the majority being clinically silent. We report a new hemoglobin variant, Hb Cook, that was found in combination with Hb E in a child of Thai origin. DNA sequencing of the beta-globin gene showed that the mutation is AAA-->ACA in codon 132, corresponding to beta 132 (H10)Lys-->Thr.
A novel type of genetic alteration, trinucleotide repeat amplification, is responsible for spinal and bulbar muscular atrophy.
DNA mismatch repair genes have been reported to play a role in the pathogenesis of hereditary nonpolyposis colorectal cancer (HNPCC). Mutations of DNA mismatch repair genes have accounted for 90% of HNPCC-related colon and endometrial tumors. These mutations have been associated with microsatellite instability (MIN). Because endometrial cancer (EC) is the most common extracolonic malignancy associated with HNPCC, we hypothesized that similar molecular alterations may occur in sporadic endometrial tumors exhibiting MIN. Mutational analysis of the MSH2 and MLH1 genes was undertaken in sporadic EC that demonstrate MIN to determine the role of these genes in the pathogenesis of sporadic ECs. Established microsatellite markers were used to determine the incidence of MIN from 28 patients with sporadic EC. MIN was observed in 32% (9 of 28) of the tumor specimens analyzed. Mutational analysis of MSH2 and MLH1 genes was performed by immunohistochemical analysis and direct sequencing of tumor specimens that exhibited MIN. All 28 tumor specimens exhibited strong nuclear staining with both MSH2 and MLH1 antibodies, suggesting the absence of mutations. Sequencing of all exons of both the MSH2 and MLH1 genes in the nine MIN-positive tumor specimens demonstrated no mutations. We conclude that the MSH2 and MLH1 genes do not play a role in the pathogenesis of sporadic endometrial cancer.
BACKGROUND: Tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) and from a subset of patients with the related Muir-Torre syndrome (MTS) exhibit a novel type of genomic instability known as microsatellite instability (MIN). In general, this form of genomic instability results from mutations that inactivate DNA mismatch repair genes. The detection of MIN in a keratoacanthoma (KA) from a patient with MTS suggested that defective mismatch repair may play a role in the pathogenesis of these neoplasms. METHODS: Randomly selected paraffin embedded KA from 53 patients and paraffin embedded tumors from an additional 12 patients diagnosed with KA and colorectal carcinoma were examined for MIN at six loci. In addition, several KA were examined for mutations within the hMSH2 gene. RESULTS: Six of the 53 randomly selected KAs had MIN at two or more loci. One of these six patients had HNPCC, whereas another had MTS. Two patients with KAs lacking MIN had colon tumors that exhibited widespread MIN, and one of these patients had MTS. Three of the 12 additional patients diagnosed with a KA and a colorectal carcinoma had at least one tumor that had MIN at two or more loci, and one of these patients had HNPCC: A 2-base pair somatic deletion in exon 3 of the hMSH2 gene was identified in one of the MIN+ KAs. CONCLUSIONS: Defective mismatch repair appears to play a role in the process of tumorigenesis in some KAs. Microsatellite instability in a KA or the cooccurrence of a colorectal carcinoma and a KA in a patient suggests that the patient may have either HNPCC or its phenotypic variant MTS.
Cytogenetic analyses have demonstrated that chromosome region 7q22-32 is commonly altered in prostate adenocarcinomas. In addition, in recent fluorescence in situ hybridization studies, we have observed that aneusomy of chromosome 7 is frequent in prostate cancer and is associated with higher tumor grade, advanced pathological stage, and early prostate cancer death. These findings suggest that genetic alterations of chromosome 7 play a significant role in the development of prostate cancer. To better define the chromosome 7 alterations, PCR analysis of 21 microsatellite loci was performed on 54 paired prostate cancer and control DNAs. Overall, chromosome 7 allelic imbalance was identified in 16 of 54 cases (30%). Allelic imbalances of loci mapped to 7q were observed in 15 of the 16 cases. The allelic imbalances were classified as losses in 15 tumors (28%) and as gains in 1 (2%) by comparative multiplex PCR analysis. The most common site of allelic loss included loci D7S523 and D7S486 at 7q31.1. A comparison with clinicopathological features of the tested tumors revealed that the allelic loss of 7q31.1 correlated with higher tumor grade (P = 0.012) and lymph node metastasis (P = 0.017). These results indicate that 7q31 may be the site of a putative suppressor gene(s) important for the pathogenesis of prostate carcinoma, and that the genetic alterations at 7q31.1 may participate in tumor progression and metastasis.
Whole chromosome uniparental disomy (UPD) for several different chromosomes has been described in individuals with phenotypes that encompass a broad range of abnormalities. We prospectively searched for UPD in 25 cytogenetically normal individuals who had one or more of the following features: nonsyndromic multiple congenital anomalies, short stature, mental retardation, or dysmorphic findings. Using highly polymorphic microsatellite repeats, biparental inheritance of at least one locus on every chromosome was found in every individual and uniparental inheritance was not detected at any locus. If UPD does exist in this clinical setting, its frequency is less than 13.7% (95% confidence interval). Our data indicate that additional studies will be required to determine the true incidence of UPD in this population.
OBJECTIVE: The outcome of patients with mild cognitive impairment is not known, yet these patients present a difficult dilemma for the clinician. This study was designed to characterize the outcome of a group of patients with mild cognitive impairment and to determine whether the presence of the epsilon 4 allele on the apolipoprotein E gene (APOE) is a predictor of that outcome. DESIGN: A prospective, longitudinal inception cohort. SETTING: General community clinic. PARTICIPANTS: A consecutive sample of 66 patients who met criteria for a diagnosis of a mild cognitive impairment and who had at least one clinical reevaluation was identified from the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry. INTERVENTIONS: We evaluated patients initially and at 12- to 18-month intervals up to 54 months using standard neurological and neuropsychological measures such as the Mini-Mental State Examination, the Dementia Rating Scale, the Wechsler Adult Intelligence Scale--Revised, the Wechsler Memory Scale--Revised, and the Free and Cued Selective Reminding Test. The APOE status of study patients was determined. MAIN OUTCOME MEASURE: The development of dementia as determined by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria. RESULTS: Sixty-six individuals had been reevaluated once (mean of 18 months), 36 individuals twice (mean of 36 months), and 22 individuals on three occasions (mean of 54 months), with conversion rates to dementia at these intervals of 24%, 44%, and 55%, respectively. A multivariate Cox regression model demonstrated that possession of an APOE epsilon 4 allele was the strongest predictor of clinical outcome. CONCLUSIONS: These data suggest the following: (1) patients with mild cognitive impairment can be clinically defined, (2) many members of this group progress to Alzheimer's disease, and (3) APOE epsilon 4 allele status appears to be a strong predictor of clinical progression.
PURPOSE: To review significant advances in the early diagnosis and treatment of medullary thyroid carcinoma in patients with the multiple endocrine neoplasia II (MEN II) syndromes, advances made possible by the application of recently discovered genetic information. DATA SOURCES: Recently published English-language literature on linkage analysis and DNA analysis in the MEN II syndromes. STUDY SELECTION: Articles on familial and sporadic forms of medullary thyroid carcinoma; pentagastrin-calcitonin determination; and genetic testing. DATA EXTRACTION: Information from recent studies on 1) the usefulness and limitations of genetic testing, especially DNA and linkage analysis, in the early diagnosis of the familial form of thyroid carcinoma and 2) the correlation between the results of genetic testing and the results of biochemical screening. DATA SYNTHESIS: Medullary thyroid carcinoma accounts for most of the morbidity and mortality among patients with the familial medullary thyroid carcinoma syndromes. Multiple endocrine neoplasia IIa and IIb and familial medullary thyroid carcinoma are inherited conditions with autosomal dominance and incomplete penetrance. Traditionally, diagnosis and screening for these conditions have been done using pentagastrin stimulation tests and plasma calcitonin determinations. Recent genetic mapping, however, has assigned the genes responsible for these tumors to the pericentromeric region of chromosome 10. Available data suggest that mutations in exon 10, 11, or 16 of the RET proto-oncogene are responsible for MEN IIa and IIb and familial non-MEN medullary thyroid carcinoma. Thus, genetic testing can identify affected members of a kindred and will probably lead to early thyroidectomy and possible cure for gene carriers. CONCLUSIONS: Early studies confirm the usefulness of DNA analysis in the diagnosis and treatment of patients with familial forms of medullary thyroid carcinoma. We review changes in the diagnosis and treatment of these patients and offer a strategy for operative intervention based on results of genetic testing.
Transthyretin (TTR) Ser 6 was originally described in a Scottish kindred without amyloidosis. This variant, arising from a G-->A transition in codon 6 that destroys an MspI site and creates a BsrI site, was present in none of 50 controls, and was therefore thought to be rare. This variant has subsequently been found in a normal human cDNA liver library and in two unrelated patients with familial amyloidosis and other TTR variants, raising the question whether it is actually a common polymorphism. To address this question, we performed PCR and restriction digestion of 574 DNA samples from people without evidence of amyloidosis or a known family history of amyloidosis. The TTR Ser 6 allele frequency was 33/558 (.060) in Caucasians (including 8/192 (.04) in North American Ashkenazic Jews, 16/218 (.07) in North American non-Jews, and 9/148 (.06) in Portuguese), 3(242 (.01) in African Americans, 0/140 in Africans, and 0/208 in Asians. These data are most suggestive of a single Caucasian founder and the known 25% admixture of "Caucasian" genes in the African-American population. Alternatively, as this variant arose from a transition at a CG dinucleotide "hot spot," it may have arisen on multiple occasions. These data indicate that TTR Ser 6 is a common non-amyloidogenic population polymorphism in Caucasians.
Recent studies have demonstrated novel alterations of microsatellite DNA in tumor tissue. The alterations, termed microsatellite instability or replication error phenotype, have now been observed in tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC), the Muir-Torre syndrome (MTS) and in an increasing number of sporadic tumors. These observations, along with the use of genetic linkage analysis, have led to the identification of at least four genetic susceptibility loci for HNPCC, hMSH2, hMLH1, hPMS1 and hPMS2, each of which are involved in DNA mismatch repair. For those tumors demonstrating microsatellite instability, several different phenotypes may exist, the significance of which is currently unknown. Defective DNA mismatch repair may have important implications for the mechanism of tumorigenesis and the clinical behavior of tumors.
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Case control studies have reported associations between specific HLA class II antigens and idiopathic dilated cardiomyopathy (DCM), suggesting that genetically regulated immune response factors may be involved in the pathogenesis of this disease. In this study, families with DCM were used to test the hypothesis that a heritable gene defect in the HLA region is the primary genetic determinant for a subset of cases. Twelve families with DCM were identified. By formal segregation analysis, the inheritance of the disease was most consistent with an autosomal dominant gene defect with incomplete penetrance. Genotyping was performed with five highly polymorphic linked dinucleotide repeat markers that span the HLA locus. Linkage analysis was used to determine whether or not these genetic markers cosegregated with the disease phenotype. Genetic linkage between the disease phenotype and a 21 cM region spanning the HLA was excluded (lod score < or = -2) in at least 60% of our families. These results indicate that a gene defect in the HLA locus region is not the primary genetic determinant of DCM in a series of familial cases. However, our data do not exclude the possibility that HLA regulated immune response factors may have a modifying effect on disease penetrance and expression.
A unique kindred manifesting medullary thyroid carcinoma and corneal nerve thickening without other aspects of the multiple endocrine neoplasia syndrome (MEN) was analyzed by linkage analysis using four highly polymorphic (CA)n repeat markers (sTCL-1, D10S141, ZNF22, and sJRH-1). Additionally, the RET protooncogene was examined for specific mutations by DNA sequence analyses in all affected family members. Screening of 11 family members spanning 4 generations revealed 7 subjects with corneal nerve thickening; of these subjects, 3 had abnormal pentagastrin-stimulated calcitonin studies, and these 3 subjects were each found to have C-cell hyperplasia or medullary thyroid carcinoma at surgery. Linkage analysis showed cosegregation of alleles (as defined by the above markers), with the presence of both corneal nerve thickening and medullary thyroid carcinoma/C-cell hyperplasia (maximum LOD score, 2.69; consistent with, but not proving linkage). DNA sequence analysis showed that none of the affected individuals had mutations in either exon 10 or 11, or in exon 16 of the RET protooncogene, regions where mutations have been described for MEN type 2A (MEN-2A) and MEN-2B families, respectively. Thus, compared to the defined syndromes of MEN-2A and MEN-2B, this kindred appears to represent a true clinical overlap syndrome whose genetic basis may be distinct from these two syndromes.
Mutations in the RET protooncogene have recently been demonstrated in families with multiple endocrine neoplasia (MEN) types 2A and 2B. We have studied pheochromocytomas from 29 individuals who had no clinical evidence of MEN-2A or -2B to determine the frequency of germline and/or somatic mutations in exons 10, 11, and 16 of the RET protooncogene. Of the 29 tumors examined, 3 (10%) were found to have a mutation in 1 of the 3 exons. These mutations were not found in the DNA from the peripheral blood from these individuals, indicating that the mutations in the tumors were somatic in origin. Although we cannot exclude the possibility of mutations in other regions of the RET protooncogene, our data suggest that 1) individuals presenting with apparently sporadic pheochromocytomas are not likely to have undiagnosed MEN-2A or -2B; and 2) somatic mutations in exons 10, 11, and 16 in the RET protooncogene contribute to the process of tumorigenesis in a small percentage of sporadic pheochromocytomas.
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The pattern of inheritance in the fragile X (fra(X)) mutation follows a multistage intergenerational process in which the premutation evolves into the full mutation and the characteristic phenotype of the fra(X) syndrome after passing through oogenesis or a postzygotic event. Findings from our multicenter study confirm a strong direct relationship between fra(X) premutation size in the mother and probability of a full mutation in offspring with the mutation. Remarkably, the best-fitting equations are nonlinear asymptotic functions. The close approximation to both the logistic model and Gompertz suggests a process of accumulation of errors in DNA synthesis, as has been proposed previously. We also note that a larger-than-expected number of daughters of transmitting males have premutations that are smaller than their fathers', and that proportion is significantly higher than the proportion of daughters whose premutations are smaller than their mothers'. Intergenerational decreases in premutation size have been reported in other trinucleotide-repeat disorders and also appear to be parent-of-origin specific. Thus, while intergenerational expansion to the full mutation in fra(X) may manifest a postzygotic event, decreases in mutation size may occur during or prior to meiosis.
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Fragile X (fra(X)) males with a standardized IQ score of 70 or higher represent a high functioning (HF) or nonretarded fra(X) male group. This group, which does not include nonpenetrant males, has received little research attention to date. Of 221 fra(X) males who had been evaluated through The Children's Hospital in Denver since 1981 and had completed cognitive or developmental testing, 29 (13%) were high functioning by the above definition. We found that HF males on the whole had a lower cytogenetic score and were younger than retarded fra(X) males, but there was no difference between these two groups in the number of typical fra(X) physical manifestations present. FMR-1 DNA testing was performed on 134 fra(X) males and methylation status was determined for 51 of these. A greater percentage of HF males had a mosaic pattern or an incompletely methylated full mutation than did retarded males. A unique DNA pattern, an unmethylated fully expanded mutation, was discovered in 3 of the highest functioning fra(X) males. Protein studies performed on 2 of these males demonstrated the presence of FMR-1 protein, albeit at lower levels than normal. FMR-1 protein was not present in retarded fra(X) males. Significant FMR-1 protein expression may be responsible for higher cognitive functioning in the 2 males with unmethylated fully expanded mutations compared to retarded fra(X) males.