Showing papers on "Anticipation (genetics) published in 2003"

Huntingtin in health and disease

Abstract: After linkage of the Huntington disease (HD) gene was found in 1983, it took ten years of work by an international group to identify the mutation in the gene interesting transcript 15 (IT15) that causes the disease (1, 2). HD is an autosomal dominant inherited neurodegenerative disease that becomes manifest in midlife and causes progressive motor, psychiatric, and cognitive dysfunction. It is invariably terminal. HD symptoms can begin as early as 2 years or as late as 90 years, although the average age of onset is in the late 30s and early 40s. If a child inherits the gene from his or her father, a phenomenon called anticipation frequently occurs, whereby the child’s age of onset is lower than the father’s (3). The IT15 gene is composed of 67 exons and encodes a protein of 3,144 amino acids, called huntingtin (2). Exon 1 contains a CAG trinucleotide repeat that encodes the amino acid glutamine, followed by another repeat that encodes proline. In unaffected individuals, there are 10‐34 CAG repeats. In those affected by HD, there are more than 40 repeats. In those with 35‐39 repeats, the disease is variably penetrant (3‐5). The age of onset of the disease varies inversely with the number of CAG repeats. Individuals with juvenile onset usually have over 55 repeats, and they usually inherit the gene from their father. Men occasionally have expanded repeats in their sperm (6). The expansion is thought to occur via slippage during the DNA replication process. Wild-type huntingtin Huntingtin contains a few domains that suggest particular functions, including WW domains and caspase cleavage sites (7, 8), but the function of the protein remains unknown. Huntingtin is expressed in the cytoplasm of most cells in the body. In the brain, expression is found predominantly in neurons (2, 9‐11). Within the cell, the protein is associated with

Intergenerational instability and marked anticipation in SCA-17.

Abstract: The authors describe an Italian family with autosomal dominant ataxia, dementia, psychiatric and extrapyramidal features, epilepsy, mild sensorimotor axonal neuropathy, and MRI findings of cerebral and cerebellar atrophy A child had a distinctive presentation with onset at 3 years, growth retardation, fast progression, and early death Molecular analysis demonstrated an expanded CAG/CAA repeat in the TBP gene (SCA-17) The repeat size was 66 triplets in the child and 53 in all the other patients

SCA2 may present as levodopa‐responsive parkinsonism

Abstract: Some kindreds with familial parkinsonism exhibit genetic anticipation, suggesting possible involvement of trinucleotide repeat expansion. Recent reports have shown trinucleotide repeat expansions in the spinocerebellar ataxia 2 (SCA2) gene in patients with levodopa-responsive parkinsonism. We tested 136 unrelated patients with familial parkinsonism for SCA2 mutations. Two probands had borderline mutations; the rest were normal. ( or=36 is pathogenic). The expanded allele segregated with neurological signs in one kindred. The absence of borderline mutations in the normal population, and the co-segregation of the expanded allele with neurological signs in one kindred suggest that SCA2 mutations may be responsible for a subset of familial parkinsonism.

Anticipation and repeat expansion in bipolar disorder.

Abstract: Anticipation is the phenomenon whereby a disease becomes more severe and/or presents with earlier onset as it is transmitted down through generations of a family. The only known mechanism for true anticipation is a class of mutations containing repetitive sequences exemplified by the pathogenic trinucleotide repeat. Studies of bipolar disorder (BPD) are consistent with the presence of anticipation and, by inference, the possibility that trinucleotide repeats contribute to this disorder, although it is possible that these data are the result of methodological problems. On the assumption that anticipation in BPD may be real, several surveys of the genome of BPD probands for large trinucleotide repeats have been conducted, as have studies of many repeat-containing candidate genes. No pathogenic triplet repeat has yet been unambiguously implicated.

XL PCR for the detection of large trinucleotide expansions in juvenile Huntington's disease.

Abstract: Juvenile Huntington's disease (HD) becomes clinically manifest before 20 years of age. The diagnosis of HD is based on family history, characteristic clinical findings, and the detection of an expansion of a CAG polyglutamine tract in the Huntingtin gene. Juvenile HD is characterized by paternal anticipation and large CAG expansions that may be missed using routine molecular analysis. We have developed an easy, rapid, and reliable modified PCR method using XL (Extra Long) PCR that allowed us to diagnose one of the youngest children reported with juvenile HD. Without this innovation we would not have been able to demonstrate the large CAG expansion. This assay could become part of a standard protocol for HD testing in molecular diagnostic laboratories.

Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the Machado-Joseph disease (SCA3) phenotype.

Abstract: Context – Machado–Joseph disease (MJD/SCA3) is an autosomal dominant cerebellar ataxia of adult onset. The variability in age at onset and the complex and heterogeneous neurologic findings indicate that MJD, caused by a major gene, is modulated by modifier factors. Objective – To study if the polymorphic CAG repeats at other loci (namely, SCA2, SCA6 and DRPLA) thus acted as modifier factors of this disease. Design – Case–control. Setting – Ambulatory care in a referral center. Patients – A convenience sample of 39 unrelated, Brazilian patients with MJD. Main outcome measures: age of onset, anticipation, clinical subtypes and neurological findings. Results – Fasciculations were associated with CAG repeat length of the long SCA2 allele (Mann–Whitney U-test, P < 0.03, after Bonferroni procedure). Other measures (age of onset, anticipation, clinical types and other neurological signs) were not associated with CAG repeat length of SCA2, SCA6 and DRPLA genes. Conclusions – The present results show that the CAG tract of SCA2 gene interferes with MJD phenotype. Further studies, with patients of other origins and with typing of other (CAG)n loci, are necessary.

Blau syndrome: a new kindred.

Abstract: Blau syndrome is a rare condition typically defined by granulomatous arthritis, skin eruption, and uveitis occurring in the absence of lung or other visceral involvement. Other characteristic physical findings include synovial cysts and camptodactyly. We describe a new kindred demonstrating autosomal dominant inheritance and anticipation.

CAG-repeat length in exon 1 of KCNN3 does not influence risk for schizophrenia or bipolar disorder: A meta-analysis of association studies

Abstract: Schizophrenia and bipolar disorder both show some evidence for genetic anticipation. In addition, significant expansion of anonymous CAG repeats throughout the genome has been detected in both of these disorders. The gene KCNN3, which codes for a small/intermediate conductance, calcium-regulated potassium channel, contains a highly polymorphic CAG-repeat array in exon 1. Initial evidence for association of both schizophrenia and bipolar disorder with increased CAG-repeat length of KCNN3 has not been consistently replicated. In the present study, we performed several meta-analyses to evaluate the pooled evidence for association with CAG-repeat length of KCNN3 derived from case-control and family-based studies of both disorders. Each group of studies was analyzed under two models, including a test for direct association with repeat length, and a test for association with dichotomized repeat-length groups. No evidence for a linear relationship between disease risk and repeat length was observed, as all pooled odds ratios approximated 1.0. Results of dichotomized allele-group analyses were more variable, especially for schizophrenia, where case-control studies found a significant association with longer repeats but family-based studies implicated shorter alleles. The results of these meta-analyses demonstrate that the risks for both schizophrenia and bipolar disorder are largely, if not entirely, independent of CAG-repeat length in exon 1 of KCNN3. This study cannot exclude the possibility that some aspect of this polymorphism, such as repeat-length disparity in heterozygotes, influences risk for these disorders. Further, it remains unknown if this polymorphism, or one in linkage disequilibrium with it, contributes to some distinct feature of the disorder, such as symptom severity or anticipation. © 2003 Wiley-Liss, Inc.

Preliminary evidence of genetic anticipation in Graves' disease.

Abstract: Despite strong epidemiologic evidence in favor of a genetic component in the etiology of Graves' disease, few hereditary risk factors have been consistently identified. The term genetic anticipation denotes a decrease in the age of onset as disease is passed through generations. In the past 5 years, genetic anticipation has been described in immune-mediated diseases such as rheumatoid arthritis and chronic inflammatory bowel disease, and recently this phenomenon has been linked to unstable expanded trinucleotide repeat sequences in several diseases. If present in Graves' disease, anticipation could provide clues to its genetic etiology. The aim of the present study was to investigate whether genetic anticipation may occur in Graves' disease. Age at diagnosis and age at ascertainment were registered and compared in 33 same-gender parent-offspring pairs with Graves' disease from multiply affected families primarily ascertained for a genetic linkage study. The mean age at diagnosis was 46.6 years (range, 16-77) in the parents and 34.1 years (range, 16-44) in the children. The difference in the mean age at diagnosis between parents and their children was 12.5 years (95% confidence interval 3.0-21.9), p = 0.010. Children were younger than their parents at diagnosis in 25 of 33 pairs (76%). In 7 pairs (21%), the parent was diagnosed after the child according to the calendar years. Essentially similar results were obtained after controlling for gender and smoking habits. In conclusion, our data suggest that patients in the second affected generation seem to acquire their disease at an earlier time in life in familial cases of Graves' disease, indicating that genetic anticipation might occur.

Anticipation and CAG*CTG repeat expansion in schizophrenia and bipolar affective disorder.

Abstract: The genetic contribution to the etiologies of schizophrenia and bipolar affective disorder (BPAD) has been considered for many decades, with twin, family, and adoption studies indicating consistently that the familial clustering of affected individuals is accounted for mainly by genetic factors. Despite the strong evidence for a genetic component, very little is understood about the underlying genetic and molecular mechanisms for schizophrenia and BPAD. In the early 1990s, after the discovery of “dynamic mutation” or “unstable DNA” as a molecular basis for the genetic anticipation observed in Huntington’s disease, myotonic dystrophy, and many others, and the recently rediscovered, albeit still controversial, evidence for genetic anticipation in major psychoses, the genetic epidemiology of schizophrenia and BPAD was re-evaluated to demonstrate strong endorsement for the unstable DNA model. Many of the non-Mendelian genetic features of schizophrenia and BPAD could be explained by the behaviour of unstable DNA, and several molecular genetic approaches became available for testing the unstable DNA hypothesis. However, despite promising findings in the mid-1990s, no trinucleotide repeat expansion has yet been identified as a cause of idiopathic schizophrenia or BPAD.

Spinocerebellar Ataxia 10 (SCA10)

Abstract: Publisher Summary Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease characterized by ataxia and epilepsy. Within a given family, the disease typically shows progressively earlier onset of the disease in successive generations with increasing severity, a phenomenon known as anticipation. The combination of relatively pure cerebellar ataxia and epilepsy is unique among inherited ataxias. The clinical diagnosis of SCA10 can be suspected based on this unique clinical feature, especially in families of Mexican descent in which SCA10 appears to be prevalent. In SCA10, the mutation is a very large expansion of an unstable ATTCT pentanucleotide repeat in intron 9 of the SCA10 gene. Thus, trinucleotide repeats are the sole class of microsatellite repeats whose expansions cause inherited ataxias, until the discovery of pentanucleotide repeat expansion in SCA10. SCA10 is the only human disease caused by expansion of a pentanucleotide repeat. This chapter presents a synoptic view of clinical features and molecular genetics of this disease, and discusses potential pathogenic mechanisms of SCA10.

Behavioral Phenotype in Myotonic Dystrophy (Steinert’s Disease)

Abstract: Myotonic dystrophy is a heritable, slowly progressive muscle disorder with involvement of multiple organ systems. Not only the muscles are affected, but also the eye, heart, gastrointestinal tract, skin, immune system, endocrine system, skull, kidneys (1), and brain (2). Moreover, these systems may be affected differentially, the age at onset is variable, as well as the course of the disease. The severity of the disease tends to increase from one generation to the next, while the age of onset decreases. This phenomenon is called anticipation. The underlying genetic mechanism of myotonic dystrophy is that of dynamic mutations, which it shares with fragile X syndrome, Huntington’s disease, and almost 20 other diseases affecting the central nervous system (NS). The molecular mechanisms of myotonic dystrophy have been partly elucidated in the last 10 years. All these characteristics make myotonic dystrophy “perhaps the most variable of human disorders” (3).

Kluyveromyces lactis Genome Mapping and Sequencing

Abstract: The complete nucleotide sequence of K. lactis is currently awaited with anticipation by the K. lactis community since it is needed to accelerate data acquisition and to provide access to new biological approaches. In the meantime, however, much information that could be very useful for research laboratories already exists in various places. The purpose of this very short review is to provide the information that exists today, and explain how and where to obtain it. Many genes can be identified through data obtained from the Genolevures program and genomic tools for genome mapping and large-scale expression have been built up, as described shortly below.