A premutation that generates a defect at crossing over explains the inheritance of fragile X mental retardation

Pembrey, Marcus; Winter, R M; Davies, Kay E.; Opitz, John M.; Reynolds, James F.

doi:10.1002/ajmg.1320210413

Cited by 121 publications

(44 citation statements)

References 28 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sequence interaction between the CYP21A and CYP2IB genes following unequal chromosome pairing has been implicated in the origin of all known pathological mutations in the 21-OH gene (2,3). Consequently, by promoting the probability ofunequal chromosome pairing, such single-repeat unit haplotypes may be envisaged as being analogous to premutations in increasing the susceptibility of developing subsequent pathological mutation (32).…”

Section: Discussionmentioning

confidence: 99%

Genesis by meiotic unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency.

Sinnott¹,

Collier²,

Costigan³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The HLA-linked human steroid 21-hydroxylase gene CYP21B and its closely homologous pseudogene CYP2JA are each normally located centromeric to a fourth component of complement (C4) (1). Although clinically heterogeneous, the disorder is always characterized by accumulation of 17-hydroxyprogesterone and by excessive androgen production, which, in the classical form of the disorder, results in masculinization ofthe external genitalia in affected female newborns.In addition, -70% ofclassical 21-OH deficiency patients show an inability to conserve dietary sodium ("salt-wasting") as a consequence of parallel deficiency in aldosterone production. The disorder maps within the class III region of the HLA complex on the short arm of chromosome 6, and molecular genetic investigations have revealed that most normal haplotypes contain, in addition to a functional 21-OH gene, CYP21B, a pseudogene, CYP21A, which shows 97% sequence homology to the functional gene. The CYP21A and CYP21B loci are positioned -=2 kilobases (kb) centromeric to the duplicated fourth component of complement (C4) genes, C4A and C4B, respectively (see Fig. 1), and the extant organization of these genes is presumed to reflect tandem duplication of an ancestral compound DNA unit -30 kb long and containing a single 21-OH gene and a single C4 gene (2, 3). Because of C4 gene length heterogeneity (4), the repeat units may be short (ca. 26 kb in length) or long (ca. 33 kb).The tandemly repeated organization of the 21-OH and C4 genes has been considered to facilitate gene deletion and addition events by unequal crossover mechanisms. Although the existence of haplotypes with variable numbers of C4 and 21-OH genes has been inferred by indirect short-range restriction mapping and complement C4 allotyping analyses, confirmation of the copy number variation has only recently been obtained by direct long-range restriction mapping approaches (5-7). Such studies have shown that gene expansion and contractions are frequent in the 21-OH/C4 gene cluster. Also, the size variation of haplotype-specific long-range restriction fragments that span the array of 21-OH and C4 genes is always consistent with integral numbers of the ca. 30-kb repeat units. Consequently, a considerable amount of circumstantial evidence has been accumulated in favor of the involvement of unequal crossover in the 21-OH/C4 gene cluster. In the present report, we present direct evidence for the occurrence of unequal crossover in this chromosomal region: a 21-OH deficiency patient has inherited a maternal haplotype that, as a result of meiotic recombination, has a ca. 30-kb de novo deletion that eliminates the functional CYP21B gene and a companion C4B gene.

show abstract

Section: Discussionmentioning

confidence: 99%

Genesis by meiotic unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency.

Sinnott¹,

Collier²,

Costigan³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Earlier models were constructed to estimate the values of parameters that shape allele and genotype frequencies at FMR1 (Vogel, 1984;Ashley and Sherman, 1995;Morris et al, 1995;Morton and Macpherson, 1992;Kolehmainen, 1994;Pembrey et al, 1985;Sherman et al, 1985;Sved and Laird, 1990). All of these models provide opportunities to infer values for key parameters, including mutation rates and fitness values.…”

Section: Introductionmentioning

confidence: 99%

Why do fragile X carrier frequencies differ between Asian and non-Asian populations?

Genereux

Laird

2013

Genes Genet. Syst.

View full text Add to dashboard Cite

Asian and non-Asian populations have been reported to differ substantially in the distribution of fragile X alleles into the normal (< 55 CGG repeats), premutation (55-199 CGG repeats), and full-mutation (> 199 CGG repeats) size classes. Our statistical analyses of data from published general-population studies confirm that Asian populations have markedly lower frequencies of premutation alleles, reminiscent of earlier findings for expanded alleles at the Huntington's Disease locus. To examine historical and contemporary factors that may have shaped and now sustain allele-frequency differences at the fragile X locus, we develop a population-genetic/epigenetic model, and apply it to these published data. We find that founder-haplotype effects likely contribute to observed frequency differences via substantially lower mutation rates in Asian populations. By contrast, any premutation frequency differences present in founder populations would have disappeared in the several millennia since initial establishment of these groups. Differences in the reproductive fitness of female premutation carriers arising from fragile X primary ovarian insufficiency (FXPOI) and from differences in mean maternal age may also contribute to global variation in carrier frequencies.

show abstract

“…The most common allele in the normal Caucasian population has 30 of these repeats, but when fully mutated the repeat tract ex-offspring through the female germline. At the 'premutation' stage carrier males, with a population frequency of around 1 in 813 (Dombrowski et al 2002), have alleles of between 55 and 200 repeats, and were for a long time thought to be phenotypically unaffected by this increased repeat length (Pembrey et al 1985). As the molecular details have been elucidated in recent years, however, it has become increasingly clear that 'premutations' and 'intermediate' alleles (∼ 41-55 repeats) represent more than a generational stepping-stone between normal allele size and full mutation (see Hagerman & Hagerman, 2004 for review).…”

Section: Introductionmentioning

confidence: 99%

Investigating the Relationship Between FMR1 Allele Length and Cognitive Ability in Children: A Subtle Effect of the Normal Allele Range on the Normal Ability Range?

Loat¹,

Craig²,

Plomin³

et al. 2006

Annals of Human Genetics

View full text Add to dashboard Cite

SummaryThe FMR1 gene contains a trinucleotide repeat tract which can expand from a normal size of around 30 repeats to over 200 repeats, causing mental retardation (Fragile X Syndrome). Evidence suggests that premutation males (55-200 repeats) are susceptible to a late-onset tremor/ataxia syndrome and females to premature ovarian failure, and that intermediate alleles (∼ 41-55 repeats) and premutations may be in excess in samples with special educational needs. We explored the relationship between FMR1 allele length and cognitive ability in 621 low ability and control children assessed at 4 and 7 years, as well as 122 students with high IQ. The low and high ability and control samples showed no between-group differences in incidence of longer alleles. In males there was a significant negative correlation between allele length and non-verbal ability at 4 years (p = 0.048), academic achievement in maths (p = 0.003) and English (p = 0.011) at 7 years, and IQ in the high ability group (p = 0.018). There was a significant negative correlation between allele length and a standardised score for IQ and general cognitive ability at age 7 in the entire male sample (p = 0.002). This suggests that, within the normal spectrum of allele length, increased repeat numbers may have a limiting influence on cognitive performance.

show abstract

A premutation that generates a defect at crossing over explains the inheritance of fragile X mental retardation

Cited by 121 publications

References 28 publications

Genesis by meiotic unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency.

Genesis by meiotic unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency.

Why do fragile X carrier frequencies differ between Asian and non-Asian populations?

Investigating the Relationship Between FMR1 Allele Length and Cognitive Ability in Children: A Subtle Effect of the Normal Allele Range on the Normal Ability Range?

Contact Info

Product

Resources

About