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Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model.
Innis JW, Mortlock D, Chen Z, Ludwig M, Williams ME, Williams TM, Doyle CD, Shao Z, Glynn M, Mikulic D, Lehmann K, Mundlos S, Utsch B
(2004) Hum Mol Genet 13: 2841-51
MeSH Terms: Animals, Base Sequence, Embryo, Mammalian, Female, Foot Deformities, Congenital, Hand Deformities, Congenital, Homeodomain Proteins, Humans, Male, Mice, Mice, Mutant Strains, Molecular Sequence Data, Pedigree, Peptides, Protein Biosynthesis, Protein Denaturation, RNA Splicing, RNA, Messenger, Recombination, Genetic, Stem Cells, Syndrome, Trinucleotide Repeats
Show Abstract · Added June 9, 2010
Polyalanine expansions in two of three large imperfect trinucleotide repeats encoded by the first exon of HOXA13 have been reported in hand-foot-genital syndrome (HFGS). Here we report additional families with expansions in the third repeat of 11 and 12 alanine residues, the latter being the largest expansion reported. We also report a patient with a novel, de novo 8-alanine expansion in the first large repeat. Thus, expansions in all three large HOXA13 polyalanine repeats can cause HFGS. To determine the molecular basis for impaired HOXA13 function, we performed homologous recombination in ES cells in mice to expand the size of the third largest polyalanine tract by 10 residues (HOXA13(ALA28)). Mutant mice were indistinguishable from Hoxa13 null mice. Mutant limb buds had normal steady-state Hoxa13 RNA expression, normal mRNA splicing and reduced levels of steady-state protein. In vitro translation efficiency of the HOXA13(ALA28) protein was normal. Thus, loss of function is secondary to a reduction in the in vivo abundance of the expanded protein likely due to degradation.
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22 MeSH Terms
Steroid hormones and hormone-related genetic and lifestyle characteristics as risk factors for benign prostatic hyperplasia: review of epidemiologic literature.
Neuhouser ML, Kristal AR, Penson DF
(2004) Urology 64: 201-11
MeSH Terms: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Aged, Alcohol Drinking, Case-Control Studies, Cohort Studies, Comorbidity, Cross-Sectional Studies, Diet, Genetic Predisposition to Disease, Gonadal Steroid Hormones, Humans, Life Style, Male, Middle Aged, Motor Activity, Obesity, Prostatic Hyperplasia, Receptors, Androgen, Receptors, Calcitriol, Risk Factors, Smoking, Steroid 17-alpha-Hydroxylase, Trinucleotide Repeats, United States
Added March 5, 2014
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24 MeSH Terms
A case-based evaluation of SRD5A1, SRD5A2, AR, and ADRA1A as candidate genes for severity of BPH.
Klotsman M, Weinberg CR, Davis K, Binnie CG, Hartmann KE
(2004) Pharmacogenomics J 4: 251-9
MeSH Terms: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Aged, Codon, Humans, Male, Muscle Tonus, Muscle, Smooth, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Prostate, Prostatic Hyperplasia, Receptors, Androgen, Trinucleotide Repeats
Show Abstract · Added March 5, 2014
In men with a clinical diagnosis of benign prostatic hyperplasia (BPH), polytomous logistic regression analysis was conducted to evaluate associations between two silent polymorphisms in SRD5A1 (codon positions 30 and 116), two polymorphisms in SRD5A2 (Val89Leu substitution and C to T transition in intron 1), a trinucleotide (CAG)n repeat in androgen receptor (AR), and an Arg492Cys substitution in ADRA1A and clinical parameters that characterize severity of BPH. Candidate gene selection was based on two mechanistic pathways targeted by pharmacotherapy for BPH: (1) androgen metabolic loci contributing to prostate growth (static obstruction); and (2) factors affecting smooth muscle tone (dynamic obstruction). Polymorphisms in SRD5A2 were not associated with severity of BPH; however, SRD5A1 polymorphisms were associated with severity of BPH. The process(es) in which these silent single-nucleotide polymorphisms (SNPs) influence BPH phenotypes is unknown and additional studies will be needed to assess whether these SNPs have direct functional consequences. The characterization of additional molecular factors that contribute to static and dynamic obstruction may help predict response to pharmacotherapy and serve to identify novel drug targets for the clinical management of BPH.
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13 MeSH Terms
The androgen receptor CAG repeat and prostate cancer risk.
Clark PE, Irvine RA, Coetzee GA
(2003) Methods Mol Med 81: 255-66
MeSH Terms: Case-Control Studies, Humans, Male, Polymerase Chain Reaction, Polymorphism, Genetic, Prostatic Neoplasms, Receptors, Androgen, Risk Factors, Trinucleotide Repeats, Tumor Cells, Cultured
Added May 27, 2014
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10 MeSH Terms
Prevalence of the fragile X syndrome in African-Americans.
Crawford DC, Meadows KL, Newman JL, Taft LF, Scott E, Leslie M, Shubek L, Holmgreen P, Yeargin-Allsopp M, Boyle C, Sherman SL
(2002) Am J Med Genet 110: 226-33
MeSH Terms: African Continental Ancestry Group, Alleles, Child, Female, Fragile X Mental Retardation Protein, Fragile X Syndrome, Gene Frequency, Humans, Male, Mutation, Nerve Tissue Proteins, Prevalence, RNA-Binding Proteins, Trinucleotide Repeats, United States
Show Abstract · Added December 10, 2013
Since the development of a molecular diagnosis for the fragile X syndrome in the early 1990s, several population-based studies in Caucasians of mostly northern European descent have established that the prevalence is probably between one in 6,000 to one in 4,000 males in the general population. Reports of increased or decreased prevalence of the fragile X syndrome exist for a few other world populations; however, many of these are small and not population-based. We present here the final results of a 4-year study in the metropolitan area of Atlanta, Georgia, establishing the prevalence of the fragile X syndrome and the frequency of CGG repeat variants in a large Caucasian and African-American population. Results demonstrate that one-quarter to one-third of the children identified with the fragile X syndrome attending Atlanta public schools are not diagnosed before the age of 10 years. Also, a revised prevalence for the syndrome revealed a higher point estimate for African-American males (1/2,545; 95% CI: 1/5,208-1/1,289) than reported previously, although confidence intervals include the prevalence estimated for Caucasians from this (1/3,717; 95% CI: 1/7,692-1/1,869) and other studies. Further population-based studies in diverse populations are necessary to explore the possibility that the prevalence of the fragile X syndrome differs among world populations.
Copyright 2002 Wiley-Liss, Inc.
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15 MeSH Terms
The exocyclic 1,N2-deoxyguanosine pyrimidopurinone M1G is a chemically stable DNA adduct when placed opposite a two-base deletion in the (CpG)3 frameshift hotspot of the Salmonella typhimurium hisD3052 gene.
Schnetz-Boutaud NC, Saleh S, Marnett LJ, Stone MP
(2001) Biochemistry 40: 15638-49
MeSH Terms: Alcohol Oxidoreductases, Bacterial Proteins, CpG Islands, DNA Adducts, DNA, Bacterial, Deoxyguanosine, Drug Stability, Frameshift Mutation, Genes, Bacterial, Malondialdehyde, Nuclear Magnetic Resonance, Biomolecular, Oligodeoxyribonucleotides, Protons, Salmonella typhimurium, Sequence Deletion, Thermodynamics, Trinucleotide Repeats
Show Abstract · Added March 5, 2014
The pyrimidopurinone adduct M1G [3-(2'-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-a]-purin-10(3H)-one], formed in DNA upon exposure to malondialdehyde or base propenals, was incorporated into 5'-d(ATCGCMCGGCATG)-3'-5'-d(CATGCCGCGAT)-3', where M = M1G. This duplex contained a two-nucleotide bulge in the modified strand, and was named the M1G-2BD oligodeoxynucleotide. It provided a model for -2 bp strand slippage deletions associated with the (CpG)3-iterated repeat hotspot for frameshift mutations from the Salmonella typhimurium hisD3052 gene. M1G was chemically stable in the M1G-2BD duplex at neutral pH. The two-base bulge in the M1G-2BD oligodeoxynucleotide was localized and consisted of M1G and the 3'-neighbor deoxycytosine. The intrahelical orientation of M1G was established from a combination of NOE and chemical shift data. M1G was in the anti conformation about the glycosyl bond. The 3'-neighbor deoxycytosine appeared to be extruded toward the major groove. In contrast, when M1G was placed into the corresponding fully complementary (CpG)3-iterated repeat duplex at neutral pH, spontaneous and quantitative ring-opening to N(2)-(3-oxo-1-propenyl)-dG (the OPG adduct) was facilitated [Mao, H., Reddy, G. R., Marnett, L. J., and Stone, M. P. (1999) Biochemistry 38, 13491-13501]. The structure of the M1G-2BD duplex suggested that the bulged sequence lacked a cytosine amino group properly positioned to facilitate opening of M1G and supports the notion that proper positioning of deoxycytosine complementary to M1G is necessary to promote ring-opening of the exocyclic adduct in duplex DNA. The structure of the M1G-2BD duplex was similar to that of the structural analogue 1,N(2)-propanodeoxyguanosine (PdG) in the corresponding PdG-2BD duplex [Weisenseel, J. P., Moe, J. G., Reddy, G. R., Marnett, L. J., and Stone, M. P. (1995) Biochemistry 34, 50-64]. The fixed position of the bulged bases in both instances suggests that these exocyclic adducts do not facilitate transient bulge migration.
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17 MeSH Terms
FMR1 and the fragile X syndrome: human genome epidemiology review.
Crawford DC, Acuña JM, Sherman SL
(2001) Genet Med 3: 359-71
MeSH Terms: European Continental Ancestry Group, Female, Fragile X Mental Retardation Protein, Fragile X Syndrome, Gene Frequency, Genetic Testing, Genome, Human, Heterozygote, Humans, Male, Mutation, Nerve Tissue Proteins, RNA-Binding Proteins, Trinucleotide Repeats
Show Abstract · Added December 10, 2013
The fragile X syndrome, an X-linked dominant disorder with reduced penetrance, is one of the most common forms of inherited mental retardation. The cognitive, behavioral, and physical phenotype varies by sex, with males being more severely affected because of the X-linked inheritance of the mutation. The disorder-causing mutation is the amplification of a CGG repeat in the 5' untranslated region of FMR1 located at Xq27.3. The fragile X CGG repeat has four forms: common (6-40 repeats), intermediate (41-60 repeats), premutation (61-200 repeats), and full mutation (>200-230 repeats). Population-based studies suggest that the prevalence of the full mutation, the disorder-causing form of the repeat, ranges from 1/3,717 to 1/8,918 Caucasian males in the general population. The full mutation is also found in other racial/ethnic populations; however, few population-based studies exist for these populations. No population-based studies exist for the full mutation in a general female population. In contrast, several large, population-based studies exist for the premutation or carrier form of the disorder, with prevalence estimates ranging from 1/246 to 1/468 Caucasian females in the general population. For Caucasian males, the prevalence of the premutation is approximately 1/1,000. Like the full mutation, little information exists for the premutation in other populations. Although no effective cure or treatment exists for the fragile X syndrome, all persons affected with the syndrome are eligible for early intervention services. The relatively high prevalence of the premutation and full mutation genotypes coupled with technological advances in genetic testing make the fragile X syndrome amenable to screening. The timing as well as benefits and harms associated with the different screening strategies are the subject of current research and discussion.
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14 MeSH Terms
Factors involved in the initial mutation of the fragile X CGG repeat as determined by sperm small pool PCR.
Crawford DC, Wilson B, Sherman SL
(2000) Hum Mol Genet 9: 2909-18
MeSH Terms: Adult, Aging, DNA, Fragile X Syndrome, Genetic Variation, Haplotypes, Humans, Leukocytes, Male, Middle Aged, Mutation, Polymerase Chain Reaction, Polymorphism, Genetic, Regression Analysis, Spermatozoa, Trinucleotide Repeats
Show Abstract · Added December 10, 2013
The fragile X syndrome is one of more than a dozen genetic diseases attributed to the amplification of a trinucleotide repeat. Despite the number of these disease loci, relatively little is known about the mechanism(s) that cause a stable allele to become unstable. Population and family studies of the fragile X CGG repeat have identified a number of factors that may play a role in repeat instability including the number of AGG interruptions, purity of the 3' and 5' end of the repeat and cis-acting factors as related to haplotype background. However, studies that assess whether these factors have an impact on the rate and magnitude of change of the repeat are lacking, mainly due to the lack of an appropriate model system. Therefore, in order to dissect the factors involved in the initial mutations of the CGG repeat, small pool (SP)-PCR was performed on DNA derived from sperm and blood from seven unaffected males whose repeat sizes range from 20 to 33. Using the SP-PCR-derived data, regression analyses suggested that components of the repeat structure such as the number of interruptions and purity of the 3' end of the repeat are important determinants of germline repeat instability. In contrast, elements other than repeat structure, such as haplotype background, seemed to have an impact on somatic repeat instability. The factors identified for either cell type, however, explained only a small portion of the variance, suggesting that other factors may be involved in this process.
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16 MeSH Terms
Fragile X CGG repeat structures among African-Americans: identification of a novel factor responsible for repeat instability.
Crawford DC, Zhang F, Wilson B, Warren ST, Sherman SL
(2000) Hum Mol Genet 9: 1759-69
MeSH Terms: 5' Untranslated Regions, African Americans, African Continental Ancestry Group, Alleles, Female, Fragile X Mental Retardation Protein, Fragile X Syndrome, Genetic Markers, Humans, Male, Nerve Tissue Proteins, Pedigree, RNA Stability, RNA-Binding Proteins, Terminal Repeat Sequences, Trinucleotide Repeats
Show Abstract · Added December 10, 2013
The cryptic CGG repeat responsible for the fragile X syndrome, located in the 5'-UTR of FMR1, is unique compared with the many other triplet repeat-causing diseases, making it ideal for identifying factors involved in repeat expansion that may be common to other triplet repeat diseases. To date, a number of factors have been identified which may influence repeat instability, including the number and position of interspersed AGGs, length of the 3' pure CGG repeat and haplotype background. However, nearly all such data were derived from studies of Caucasians. Using a large African-American population, we present the only comprehensive examination of factors associated with CGG repeat instability in a non-Caucasian population. Among Caucasians, susceptible alleles were thought to come from those in the intermediate repeat range (41-60 repeats); however, we find that susceptible alleles may come from a larger repeat pool (35-60 repeats) and are better defined by their pure CGG repeat and/or -presence of only one AGG interruption. These results demonstrate the existence of different susceptible alleles among world populations and may account for the similar prevalence of the fragile X syndrome in African-Americans compared with Caucasians despite the lower frequency of inter-mediate sized alleles in the African-American population. Finally, we show that repeat structures among unaffected African-Americans with the most frequent fragile X haplotype background are either pure or contain a single distal interruption. We propose that the lack of a proximal most interruption is a novel factor involved in CGG repeat instability.
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16 MeSH Terms
Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1.
Gunter C, Paradee W, Crawford DC, Meadows KA, Newman J, Kunst CB, Nelson DL, Schwartz C, Murray A, Macpherson JN, Sherman SL, Warren ST
(1998) Hum Mol Genet 7: 1935-46
MeSH Terms: Adenine Nucleotides, Alleles, Animals, Fragile X Mental Retardation Protein, Fragile X Syndrome, Gene Frequency, Genetic Markers, Guanine Nucleotides, Haplotypes, Humans, Introns, Linkage Disequilibrium, Male, Microsatellite Repeats, Nerve Tissue Proteins, Pan troglodytes, Polymorphism, Genetic, Polymorphism, Single-Stranded Conformational, RNA-Binding Proteins, Trinucleotide Repeats
Show Abstract · Added December 10, 2013
In at least 98% of fragile X syndrome cases, the disease results from expansion of the CGG repeat in the 5' end of FMR1. The use of microsatellite markers in the FMR1 region has revealed a disparity of risk between haplotypes for CGG repeat expansion. Although instability appears to depend on both the haplotype and the AGG interspersion pattern of the repeat, these factors alone do not completely describe the molecular basis for the linkage disequilibrium between normal and fragile X chromosomes, in part due to instability of the marker loci themselves. In an effort to better understand the mechanism of dynamic mutagenesis, we have searched for and discovered a single nucleotide polymorphism in intron 1 of FMR1 and characterized this marker, called ATL1, in 564 normal and 152 fragile X chromosomes. The G allele of this marker is found in 40% of normal chromosomes, in contrast to 83% of fragile X chromosomes. Not only is the G allele exclusively linked to haplotypes over-represented in fragile X syndrome, but G allele chromosomes also appear to transition to instability at a higher rate on haplotypes negatively associated with risk of expansion. The two alleles of ATL1 also reveal a highly significant linkage disequilibrium between unstable chromosomes and the 5' end of the CGG repeat itself, specifically the position of the first AGG interruption. The data expand the number of haplotypes associated with FMR1 and specifically allow discrimination, by ATL1 alleles, of single haplotypes with differing predispositions to expansion. Such haplotypes should prove useful in further defining the mechanism of dynamic mutagenesis.
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20 MeSH Terms