Influence of the X-Chromosome on Neuroanatomy: Evidence from Turner and Klinefelter Syndromes

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 03/2014; 34(10):3509-16. DOI: 10.1523/JNEUROSCI.2790-13.2014
Source: PubMed

ABSTRACT Studies of sex effects on neurodevelopment have traditionally focused on animal models investigating hormonal influences on brain anatomy. However, more recent evidence suggests that sex chromosomes may also have direct upstream effects that act independently of hormones. Sex chromosome aneuploidies provide ideal models to examine this framework in humans, including Turner syndrome (TS), where females are missing one X-chromosome (45X), and Klinefelter syndrome (KS), where males have an additional X-chromosome (47XXY). As these disorders essentially represent copy number variants of the sex chromosomes, investigation of brain structure across these disorders allows us to determine whether sex chromosome gene dosage effects exist. We used voxel-based morphometry to investigate this hypothesis in a large sample of children in early puberty, to compare regional gray matter volumes among individuals with one (45X), two (typically developing 46XX females and 46XY males), and three (47XXY) sex chromosomes. Between-group contrasts of TS and KS groups relative to respective sex-matched controls demonstrated highly convergent patterns of volumetric differences with the presence of an additional sex chromosome being associated with relatively decreased parieto-occipital gray matter volume and relatively increased temporo-insular gray matter volumes. Furthermore, z-score map comparisons between TS and KS cohorts also suggested that this effect occurs in a linear dose-dependent fashion. We infer that sex chromosome gene expression directly influences brain structure in children during early stages of puberty, extending our understanding of genotype-phenotype mechanisms underlying sex differences in the brain.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Male and female human embryos develop identically during the first phase of gestation. The indifferent gonads then differentiate into ovaries or testes and soon begin to secrete their characteristic hormones. If ovaries (or no gonads) are present the final phenotype is female; thus no gonadal hormones are required for female development during embryogenesis. Two hormones of the fetal testis--Mullerian regression hormone and testosterone--are responsible for the formation of the male phenotype. Analysis of fibroblasts from the skin of patients with abnormalities of sexual development due to single gene defects shows that testosterone is responsible for virilization of the male internal genital tract, that its derivative dihydrotestosterone causes development of the male external genitalia, and that both hormones act in the embryo by the same receptor mechanisms operative in postnatal life.
    Science 04/1981; 211(4488):1278-84. DOI:10.1126/science.7010602 · 31.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, the magnitude, consistency, and stability across time of cognitive sex differences have been questioned. The present study examined these issues in the context of spatial abilities. A meta-analysis of 286 effect sizes from a variety of spatial ability measures was conducted. Effect sizes were partitioned by the specific test used and by a number of variables related to the experimental procedure in order to achieve homogeneity. Results showed that sex differences are significant in several tests but that some intertest differences exist. Partial support was found for the notion that the magnitude of sex differences has decreased in recent years. Finally, it was found that the age of emergence of sex differences depends on the test used. Results are discussed with regard to their implications for the study of sex differences in spatial abilities.
    Psychological Bulletin 04/1995; 117(2):250-70. DOI:10.1037/0033-2909.117.2.250 · 14.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Most neuropsychological studies of cases of chromosomal abnormalities report associations with disorders or disabilities. Studies of Turner's Syndrome (TS), in which their is functional absence of the information carried on the short arm of the second X chromosome, have emphasised disorders of spatial skill and potential abnormality of the parietal lobes or right hemisphere. In contrast, language skills have received little investigation despite suggestions by Shaffer (1962) of considerable verbal skill. This paper reports on an analysis of reading skill, in girls with TS. The girls with TS attained reading levels higher than those predicted on the basis of their age and intelligence. Moreover, they attained significantly higher reading levels than controls. Unlike many previous studies of hyperlexia, reading comprehension was also better than controls. The hyperlexia of the girls with TS was characterised by strength in both lexical reading systems, as assessed by the ability to read irregular words, and strength in alphabetical or phonological reading skills, as assessed by the ability to read long unfamiliar regular words. Hyperlexia need not therefore co-occur with comprehension difficulties nor need it reflect strength in only part of the reading system. In TS it appears to represent a genuine hyperdevelopment of a skill. The strength of reading skill counterbalances the spatial difficulties of a comparable sample of girls with TS (Temple and Carney, 1995), and with other verbal skills may potentially be exploited in remedial enterprises.
    Cortex 07/1996; 32(2):335-45. · 6.04 Impact Factor