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PubMed1998

[Hereditary neurological diseases caused by amplification of triplet repetitions].

NEW TYPE OF MUTATION: Repeated sequences of nucleotide triplets can cause two groups of diseases. GROUP I DISEASES: These diseases result from an expansion of a noncoding portion of a gene which may be repeated more than 1000 times. This group includes several multisystem diseases such as the fragile X syndrome and its variants, Steinert's disease and Friedreich's disease in which nervous system disorders are not always predominant. The molecular mechanism of the cellular disorder is probably related to a nonfunctional abnormal protein. GROUP II DISEASES: Huntington's disease, spinobulbar amyotrophy or Kennedy's disease, dentato-rubo-pallidolusian atrophy and spinocerebellar ataxias 1, 2, 3, 6, and 7 are characterized by local expansion of the coding part of a gene. This low-amplitude expansion always involves the CAG triplet and leads to expression of a protein with an abnormal number of glutamines, producing typical neurodegenerative disease almost exclusively limited to the nervous system. The underlying mechanism of the neuronal suffering is probably the production of an abnormal but functional protein. The causes of this type of mutation remain unclear. PERSPECTIVES: Positive diagnosis is now possible with DNA sequencing. While antenatal diagnosis offers essential information for family genetic counselling there is no perspective of therapeutic propositions for the near future. The problems raised by presymptomatic diagnosis must not be underestimated.

DNA Mutational Analysis↗
PubMed1999

The molecular genetic bases of the progressive myoclonus epilepsies.

Among the epilepsies, the progressive myoclonus epilepsies (PMEs) form a heterogeneous group of rare diseases characterized by myoclonus, epilepsy, and progressive neurologic deterioration, particularly dementia and ataxia. The success of the Human Genome Project and the fact that most PMEs are inherited through a mendelian or mitochondrial mode have resulted in important advances in the definition of the molecular basis of PME. The gene defects for the most common forms of PME (Unverricht-Lundborg disease, the neuronal ceroid lipofuscinoses, Lafora disease, type I sialidosis, and myoclonus epilepsy with ragged-red fibers) have been either identified or mapped to specific chromosome sites. Unverricht-Lundborg disease has been shown to be caused by mutations in the gene that codes for cystatin B, an inhibitor of cysteine protease. The most common mutation in Unverricht-Lundborg disease is an expansion of a dodecamer repeat located in a noncoding region upstream of the transcription start site of the cystatin B gene, making it the first human disease associated with instability of a dodecamer repeat. Juvenile neuronal ceroid lipofuscinosis is caused by mutations in the CLN3 gene, a gene of unknown function that encodes a 438-amino-acid protein of possible mitochondrial location. Other forms of neuronal ceroid lipofuscinosis that occur as PME and Lafora disease have been mapped by means of linkage analysis, but the corresponding gene defects remain unknown. Sialidosis has been shown to be caused by mutations in the sialidase gene, and myoclonus epilepsy with ragged-red fibers is well known to be caused by mutations in the mitochondrial gene that codes for tRNA(Lys). How the different PME gene defects described produce the various PME phenotypes, including epileptic seizures, remains unknown. The development of animal models that bear these mutations is needed to increase our knowledge of the basic mechanisms involved in the PMEs. This knowledge should lead to the development of new and effective forms of therapy, which are especially lacking for the PMEs.

Chromosome Mapping↗
PubMedDate not supplied

[Juvenile form of Huntington's disease--diagnostic problems].

Variability of clinical manifestation is an important feature of Huntington's disease (HD). It is due to the high instability of CAG sequences within a coding region of IT15 gene. We present five pedigrees in which apart from the adult form of HD the juvenile form of the disease affected some of the patients--as a result of genetic anticipation. Molecular analysis confirmed the well known fact that anticipation, which manifests itself by earlier onset of the disease in the subsequent generations, is strongly correlated with the degree of amplification of (CAG)n repeats in IT15 gene. An interesting feature of the presented data is the fact, that expansion of CAG repeats occurred not only at the paternal but also at the maternal transmission of the mutation. Some children in the presented HD pedigrees presented other neurological disturbances which could be suspected of HD; a molecular analysis revealing normal number of CAG repeats, enabled us to avoid misdiagnosis. The presented data provide evidence that clinical diagnosis of HD, particularly in cases with not very characteristic clinical picture--is not possible without DNA analysis--even in the families undoubtfully affected with the disease.

Adolescent↗
PubMed2005

Reduced genetic variation occurs among genes of the highly clonal plant pathogen Xanthomonas axonopodis pv. vesicatoria, including the effector gene avrBs2.

The bacterial plant pathogen Xanthomonas axonopodis pv. vesicatoria, also known as Xanthomonas campestris pv. vesicatoria group A, is the causal agent of bacterial spot in pepper and tomato. In order to test different models that may explain the coevolution of avrBs2 with its host plants, we sequenced avrBs2 and six chromosomal loci (total of 5.5 kb per strain) from a global sample of 55 X. axonopodis pv. vesicatoria strains collected from diseased peppers. We found an extreme lack of genetic variation among all X. axonopodis pv. vesicatoria genomic loci (average nucleotide diversity, pi = 9.1 x 10(-5)), including avrBs2. This lack of diversity is consistent with X. axonopodis pv. vesicatoria having undergone a recent population bottleneck and/or selective sweep followed by population expansion. Coalescent analysis determined that approximately 1.4 x 10(4) to 7.16 x 10(4) bacterial generations have passed since the most recent common ancestor (MRCA) of the current X. axonopodis pv. vesicatoria population. Assuming a range of 50 to 500 bacterial generations per year, only 28 to 1,432 years have passed since the MRCA. This time frame coincides with human intervention with the pathogen's host plants, from domestication to modern agricultural practices. Examination of 19 mutated (loss-of-function) avrBs2 alleles detected nine classes of mutations. All mutations affected protein coding, while no synonymous changes were found. The nature of at least one of the avrBs2 mutations suggests that it may be possible to observe one stage of an evolutionary arms race as X. axonopodis pv. vesicatoria responds to selection pressure to alter avrBs2 to escape host plant resistance.

Alleles↗
PubMed2006

Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype.

RATIONALE: Congenital central hypoventilation syndrome (CCHS), a unique disorder of respiratory control associated with Hirschsprung disease (HSCR) and tumors of neural crest origin, results from polyalanine repeat expansion mutations in the paired-like homeobox (PHOX)2B gene in more than 90% of cases, and alternative PHOX2B mutations in remaining cases. OBJECTIVES: To characterize CCHS-associated nonpolyalanine repeat mutations in PHOX2B, evaluate genotype-phenotype relationships, and compare clinical features of CCHS in cases with nonpolyalanine repeat mutations to those with polyalanine expansion mutations. METHODS: DNA from probands was analyzed by polymerase chain reaction for the common polyalanine repeat expansion. If no expansion was present, coding regions and intron-exon boundaries of PHOX2B were sequenced. When possible, parents and siblings were screened for the mutation found in the proband. RESULTS: Fourteen nonpolyalanine repeat mutations, including missense, nonsense, and frameshift mutations, and 170 polyalanine repeat mutations were identified in 184 CCHS probands. Both incomplete penetrance and parental mosaicism were observed within the family members of probands with nonpolyalanine repeat mutations. Increased prevalence of continuous ventilatory dependence, HSCR, and neural crest tumors was seen in the nonpolyalanine repeat group compared to those with polyalanine repeat mutations. CONCLUSIONS: These data suggest that nonpolyalanine repeat mutations produce more severe disruption of PHOX2B function. Patients carrying these mutations should be evaluated for HSCR and neural crest tumors. Because incomplete penetrance can occur in families of CCHS probands with PHOX2B mutations, genetic screening of appropriate family members is indicated to evaluate reproductive risk and because asymptomatic mutation carriers may be at risk for developing alveolar hypoventilation.

Codon, Nonsense↗
PubMed2006

The Wnt code: cnidarians signal the way.

Cnidarians are the simplest metazoans with a nervous system. They are well known for their regeneration capacity, which is based on the restoration of a signalling centre (organizer). Recent work has identified the canonical Wnt pathway in the freshwater polyp Hydra, where it acts in organizer formation and regeneration. Wnt signalling is also essential for cnidarian embryogenesis. In the sea anemone Nematostella vectensis 11 of the 12 known wnt gene subfamilies were identified. Different wnt genes exhibit serial and overlapping expression domains along the oral-aboral axis of the embryo (the 'wnt code'). This is reminiscent of the hox code (cluster) in bilaterian embryogenesis that is, however, absent in cnidarians. It is proposed that the common ancestor of cnidarians and bilaterians invented a set of wnt genes that patterned the ancient main body axis. Major antagonists of Wnt ligands (e.g. Dkk 1/2/4) that were previously known only from chordates, are also present in cnidarians and exhibit a similar conserved function. The unexpectedly high level of genetic complexity of wnt genes evolved in early multi-cellular animals about 650 Myr ago and suggests a radical expansion of the genetic repertoire, concurrent with the evolution of multi-cellularity and the diversification of eumetazoan body plans.

Animals↗
PubMed1999

[Unstable expansion of CAG repeat and molecular mechanism of neurodegeneration in SCA1].

SCA1 is caused by unstable expansion of CAG repeat in the coding region of a novel gene located on chromosome 6p23. Expansion up to 40-80 repeats develop the disorder, and the repeat length correlates with age at onset, rate of progression, or clinical severity. Expanded SCA1 allele is unstable during meiosis and mitosis, which is related to anticipation phenomenon and somatic mosaicism, respectively. SCA1 gene is expressed ubiquitously. In neurons, its transcript (ataxin-1) localizes mostly in nucleus. Ataxin-1 with expanded glutamine repeat is highly ubiquinated and forms aggregation within nucleus. These findings in clinical genetical, and cell biology are all common in other polyglutamine disorders, highly indicating that common molecular mechanisms underlie in these disorders. Based on these background, recent progress in the research for SCA1 is reviewed.

Animals↗
PubMed2004

Genetic diversity patterns in the SR-BI/II locus can be explained by a recent selective sweep.

The human scavenger receptor class B type I (SR-BI and splice variant SR-BII) plays a central role in HDL cholesterol metabolism and represents a candidate gene for a number of related diseases. We examined the genetic diversity of its coding and flanking regions in a sample of 178 chromosomes from individuals of European, African, East Asian (including Southeast Asian), Middle-Eastern as well as Amerindian descent. Nine of the 14 polymorphisms observed are new. Four of the five variants causing amino acid replacements, G2S, S229G, R484W, and G499R, are likely to affect protein structure and function. SR-BI/BII diversity is partitioned among 19 haplotypes; all but one interconnected by single mutation or a recombination event. Such tight haplotype network and the unusual geographic partitioning of this diversity, high not only in Africa but in East Asia as well, suggests its recent origin and possible effect of selection. Coalescent analysis infers a relatively short time to the most recent common ancestor and points to population expansion in Africa and East Asia. These two continents differ significantly in pairwise F(ST) values, differing as well from a single cluster formed by Europe, Middle East and America. In the context of findings for similarly analyzed other loci, we propose that a selective sweep at the origin of modern human populations could explain the low level of ancestral SR-BI/II diversity. The unusually deep split between Africa and Asia, well beyond the Upper Paleolithic when inferred under neutrality, is consistent with subsequent geographical and demographic expansion favoring the accumulation of new variants, especially in groups characterized by large effective population sizes, such as Asians and Africans. The relevance of such partitioning of SR-BI/II diversity remains to be investigated in genetic epidemiological studies which can be guided by the present findings.

CD36 Antigens↗
PubMed1994

T4 phage evolution data in terms of a time-dependent Topal-Fresco mechanism.

A physical interpretation of the Topal-Fresco [Nature 263, 285 (1976)] model for spontaneous base substitutions suggests that hydrogen-bonded DNA protons satisfy the criteria for a classical noninteracting isolated system. Accessible states for duplex G-C protons include the keto-amino state and the six complementary enol-imine isomers. Hydrogen-bonded enol and imine protons occupy symmetric double-minima created by the two sets of indistinguishable electron lone pairs and a single proton belonging to each enol-imine end group. These protons will consequently participate in coupled quantum mechanical flip-flop, tunneling back and forth between symmetric energy wells. This results in a quantum mixing of proton energy states where the lowest energy state will be a linear combination of available G-C isomers. The resulting conclusion is that metastable keto-amino G-C protons will populate accessible enol-imine stationary states at rates governed by quantum laws of statistical equilibrium, consistent with achieving the lowest energy condition for duplex G-C protons. Enol-imine G-C stationary states are bound more tightly, of the order of 3 to 12 kcal/mol, which requires a modified mode of Topal-Fresco replication that will inhibit reequilibration of enol and imine G and C template isomers and, thus, promote the formation of complementary mispairs. The model is demonstrated on time-dependent base substitutions expressed by T4 phage DNA systems where data are consistent with model explanations, including the prediction that time-dependent evolutionary transversion sites will exhibit both G-C-to-T-A and G-C-to-C-G transversions at replication, due to proton flip-flop alteration of G template genetic specificity. The observation that A-T sites are resistant to time-dependent evolutionary base substitutions, expressed exclusively at G-C sites, allows codons to be classified as either evolutionary sensitive (16 codons) or evolutionary resistant (8 codons). These criteria provide possible explanations for expansion properties of the CGG fragile X sequences. Enol-imine G-C stationary states appear to have been misdiagnosed as deamination of cytosine and oxidation of guanine to 8-hydroxy-guanine.

Amino Acids↗
PubMed2006

Atrichia with papular lesions resulting from a novel insertion mutation in the human hairless gene.

BACKGROUND: Congenital atrichia with papular lesions is a rare, recessively inherited condition of total alopecia, characterized clinically by complete and irreversible hair loss, which begins shortly after birth with the development of the papular lesions of keratin-filled cysts over an extensive area of the body. Mutations in the human hairless (HR) gene have been implicated in the pathogenesis of this disorder. OBJECTIVE: To search for a mutation in human HR in a family with congenital atrichia. METHODS: Linkage analysis was carried out using genotyping markers closely linked to congenital atrichia locus on chromosome 8p12. Subsequently, human HR was sequenced to identify a disease-causing mutation. RESULTS: A novel 11 bp insertion mutation, G202 (InsCTTCCCCCAGG), in exon 2 of the hairless gene was identified in a Pakistani consanguineous family affected by congenital atrichia. The insertion results in the expansion of 11 bp tandem repeat, which introduces a translational frameshift leading to downstream premature termination codon. CONCLUSIONS: This mutation is the first insertion mutation identified in the coding sequence of human HR. This extends our knowledge of mutations in HR that define the pathogenic basis of this disease.

Alopecia↗
PubMed2004

Fragile X mental retardation syndrome: from pathogenesis to diagnostic issues.

The Fragile X (FRAXA) syndrome is the most common cause of familial (monogenic) mental retardation and is widespread in human populations. This syndrome is characterised by an unusual mode of transmission for an X-linked disease. In affected families, one frequently finds clinically normal transmitting males, whose daughters - also clinically normal - have a high risk of having affected children. The risk of developing the disease (penetrance) thus appears to increase in successive generations of the same family through maternal transmission. As shown by molecular cloning of the fragile X locus, Fragile X mutations are unstable expansions of a CGG trinucleotide repeat, located in the first exon (non-protein-coding) of the FMR1 gene (for Fragile X Mental Retardation). Two main types of mutation are observed in affected families. A full mutation is found in patients with mental retardation and corresponds to large expansions of the repeat. Premutations are moderate expansions and are found in normal transmitting males and in the majority of clinically normal carrier females. About 15% of patients show a mosaic pattern consisting of both full mutations and premutations. Although analysis of the CGG expansion has led to the establishment of reliable tests for diagnosis and genetic counseling of Fragile X syndrome, care must be exercised to use these tools to answer the concerns of the families and avoid doing harm. In our opinion, testing in children should be restricted to those who show a developmental delay, cognitive deficits and/or abnormal behavior evocative of the syndrome. A carrier diagnosis in a girl who is clinically normal should probably only be performed at an age where she can understand the consequences for family planning and the options of prenatal diagnosis. When testing children with borderline cognitive deficits, a positive diagnosis should be used to improve educational strategies for the children - and not to stigmatise them.

Child↗
PubMed2005

TATA-binding protein in neurodegenerative disease.

TATA binding protein (TBP) is a general transcription factor that plays an important role in initiation of transcription. In recent years evidence has emerged implicating TPB in the molecular mechanism of a number of neurodegenerative diseases. Wild type TBP in humans contains a long polyglutamine stretch ranging in size from 29 to 42. It has been found associated with aggregated proteins in several of the polyglutamine disorders. Expansion in the CAA/CAG composite repeat beyond 42 has been shown to cause a cerebellar ataxia, SCA17. The involvement of such an important housekeeping protein in the disease mechanism suggests a major impact on the functioning of cells. The question remains, does TBP contribute to these diseases through a loss of normal function, likely to be catastrophic to a cell, or the gain of an aberrant function? This review deals with the function of TBP in transcription and cell function. The distribution of the polyglutamine coding allele lengths in TBP of the normal population and in SCA17 is reviewed and an outline is given on the reported cases of SCA17. The role of TBP in other polyglutamine disorders will be addressed as well as its possible role in other neurodegenerative diseases.

Animals↗
PubMed1975

Germ line basis for antibody diversity.

Each antibody polypeptide chain is the product of a gene pair comprising one constant (C) gene coding for that portion of the chain common to all chains of the same type and one variable (V) gene coding for the sequence unique to each chain. Previous evidence indicates that the haploid genome has a single copy of each distinct C gene and that for expression a gene pair is formed with any one of a family of V genes present in the same haploid genome. Hybridization of purified mRNA coding for immunoglobulin heavy chain (mRNA-H) with a vast excess of DNA confirms the existence of a single C gene of each type and multiple V genes. A large number (of the order of 104) of V genes would be consistent with the hybridization results. This suggests considerable V gene redundancy which is a predictable property of a multiple V gene family maintained by expansion and contraction mechanisms. The mRNA-H used in these hybridization studies was isolated by a specific interaction with immunoglobulin. The same method has also been used to isolate a nuclear precursor of mRNA-H. Identification of this precursor strengthens the evidence for the direct joining of the V and C gene pair at the DNA level prior to transcription.

Amino Acid Sequence↗
PubMed1997

Genetic alterations of androgen receptor gene in Japanese human prostate cancer.

In order to determine the significance of androgen receptor (AR) gene mutations for Japanese prostate cancers, we examined the entire coding region, from exon A to H, in 36 primary lesions. Five in stage A, 12 in stage B, six in stage C and 13 in stage D were subjected to PCR-SSCP analysis for genomic DNA and nucleotide sequencing. Mutations were detected in five samples (14%). Two in stage D and refractory to anti-androgen treatment showed mis-sense mutations. The other three showed changes in the length of the CAG repeat in exon A, with an expansion or a contraction of one repeat unit. However, no association with changes in AR function was indicated because they had not been refractory to hormone therapy. Since these latter three tumors were associated with microsatellite instability, the changes might have been the result of an impairment of mismatch repair. This study indicates that AR gene mutations play a role, in only a subset of prostate cancer patients, in a treatment-refractory state.

Adult↗
PubMed2026

Establishment of four induced pluripotent stem cell lines (IGIBi028-A, IGIBi029-A, IGIBi030-A, and IGIBi031-A) from peripheral blood derived cells of Spinocerebellar ataxia Type 12 patients.

Spinocerebellar ataxia type 12 (SCA12) is a progressive late-onset neurodegenerative disorder caused by expansion of ≥ 43 trinucleotide CAG repeats in the upstream non-coding region of the PPP2R2B gene at locus 5q32 (SCA12; OMIM#604326). Clinically SCA12 patients predominately present hand tremor, gait ataxia, tremulous voice and other neurological and psychiatric features. Neuroimaging reveals degenerative changes in the cerebral cortex and cerebellum, however, the underlying disease mechanism at molecular level is still incompletely understood. Here we report generation of four induced pluripotent stem cells (iPSCs) of SCA12 patients. The established lines were positive for PPP2R2B-CAG expansion mutation and showed expression of undifferentiated hPSC state markers, three germ layer differentiation potential, normal genetic integrity and contamination-free culture.

Humans↗
PubMedDate not supplied

A novel JC virus variant found in the Highlands of Papua New Guinea has a 21-base pair deletion in the agnoprotein gene.

OBJECTIVES: This paper describes a unique JC virus (JCV) variant recovered from the Highlands of Papua New Guinea that contains an inframe 21-bp deletion in the agnoprotein gene. We characterize the mutation and suggest possible roles for the deletion in JCV evolution. STUDY DESIGN/METHODS: JCV DNA was extracted from urine and polymerase chain reaction (PCR) amplified using whole genome primers. PCR products were cloned, and multiple clones were sequenced. The JCV agnogene was PCR amplified to verify the presence of the agnogene deletion. RESULTS: This mutation creates a 21-bp deletion near the 3' end, which alters the predicted secondary structure of the messenger RNA and changes local codon usage at the 3' end of the agnogene. Protein secondary structure predictions suggest the deleted portion of the agnoprotein may be a flexible surface feature. CONCLUSIONS: We describe the first stable coding region deletion in JCV that presumably signifies a single evolutionary event that led to the split from other Highlands viral groups and occurred well after the human expansions that led to the peopling of the Southwest Pacific.

Base Sequence↗
PubMed2002

Novel genetic association of Wegener's granulomatosis with the interleukin 10 gene.

OBJECTIVE: Wegener's granulomatosis (WG) is a necrotizing vasculitis characterized by clonal expansions of T cells and production of antibodies against proteinase 3. The disease is associated with expanded dinucleotide repeats in the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene, suggesting that genetic variation(s) in T cell related gene(s) could contribute to the T cell hyperactivity in WG. We investigated the polymorphisms in the genes of 2 cytokines, interleukin 4 (IL-4) and IL-10, which are essential for the polarization of T cells towards Th2 development and for the Ig production by B cells. METHODS: Polymorphisms in the genes coding for IL-10 and IL-4 were analyzed in 32-36 Swedish Caucasian patients and 109 ethnically matched healthy individuals. RESULTS: There was no association with the IL-4 gene. A CA repeat polymorphism in IL-10 gene, IL-10.G, was associated with the disease. This polymorphism has earlier been associated with high autoantibody production. CONCLUSION: Our results indicate that the IL-10 gene may influence the disease, perhaps by influencing the production of autoantibodies.

Adult↗
PubMed2006

Selection of early-occurring mutations dictates hormone-independent progression in mouse mammary tumor lines.

Mice harboring three mouse mammary tumor virus (MMTV) variants develop pregnancy-dependent (PD) tumors that progress to pregnancy-independent (PI) behavior through successive passages. Herein, we identified 10 predominant insertions in PI transplants from 8 independent tumor lines. These mutations were also detected in small cell populations in the early PD passages. In addition, we identified a new viral insertion upstream of the gene Rspo3, which is overexpressed in three of the eight independent tumor lines and codes for a protein very similar to the recently described protein encoded by Int7. This study suggests that during progression towards hormone independence, clonal expansion of cells with specific mutations might be more relevant than the occurrence of new MMTV insertions.

Animals↗