Turner syndrome (TS) is the human genetic disorder involving females who lack all or part of one X chromosome. The complex phenotype includes ovarian failure, a characteristic neurocognitive profile, and typical physical features. TS features are associated not only with complete monosomy X but also with partial deletions of either the short (Xp) or long (Xq) arm (partial monosomy X). Impaired visual-spatial/perceptual abilities are characteristic of TS children and adults of varying races and socioeconomic status, but global developmental delay is uncommon. The constellation of neurocognitive deficits observed in TS is most likely multifactorial and related to a complex interaction between genetic abnormalities, hormonal deficiencies, and other unspecified determinants of cognitive ability. Furthermore, an additional genetic mechanism, imprinting, may contribute to cognitive deficits associated with monosomy X. The investigators propose in the current study to delineate the genetic factors that account for the Turner syndrome neurocognitive phenotype in adults by 1) mapping the TS-associated neurocognitive phenotypes in partial monosomy X women, 2) collecting parent-of-origin data from adult Turner syndrome subjects for imprinting studies, and 3) contrasting women who have both genetic (X chromosome) and hormonal abnormalities with women who have only a hormonal abnormality (idiopathic premature ovarian failure). These studies will test the hypothesis from preliminary data that cognitive dysfunction associated with monosomy X maps to distal Xp. As a relatively common genetic disorder with well-defined manifestations, TS presents an opportunity to investigate genetic factors that influence female cognitive development. There is potentially informative genetic and phenotypic variation among TS subjects with partial X deletions. Careful clinical and molecular characterization of these unusual subjects, who represent """"""""experiments in nature,"""""""" could link the TS phenotype of impaired visual spatial/perceptual ability to specific X chromosome regions. Turner syndrome is an excellent model for such phenotype mapping studies because of its prevalence, the well-characterized phenotype, and the wealth of molecular resources available for the X chromosome. Phenotype mapping of X deletions will be helpful for genetic counseling. Characterization of specific TS causative genes would provide insight into the pathophysiology of 45,X, Turner syndrome, as well as the process of normal neurocognitive development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042777-02
Application #
6540530
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Nichols, Paul L
Project Start
2001-05-17
Project End
2006-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
2
Fiscal Year
2002
Total Cost
$420,543
Indirect Cost
Name
Thomas Jefferson University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Beaton, Elliott A; Stoddard, Joel; Lai, Song et al. (2010) Atypical functional brain activation during a multiple object tracking task in girls with Turner syndrome: neurocorrelates of reduced spatiotemporal resolution. Am J Intellect Dev Disabil 115:140-56
Zinn, Andrew R; Kushner, Harvey; Ross, Judith L (2008) EFHC2 SNP rs7055196 is not associated with fear recognition in 45,X Turner syndrome. Am J Med Genet B Neuropsychiatr Genet 147B:507-9
Simon, T J; Takarae, Y; DeBoer, T et al. (2008) Overlapping numerical cognition impairments in children with chromosome 22q11.2 deletion or Turner syndromes. Neuropsychologia 46:82-94
Campos-Barros, Angel; Benito-Sanz, Sara; Ross, Judith L et al. (2007) Compound heterozygosity of SHOX-encompassing and downstream PAR1 deletions results in Langer mesomelic dysplasia (LMD). Am J Med Genet A 143A:933-8
Bondy, Carolyn A; Matura, Lea Ann; Wooten, Nicole et al. (2007) The physical phenotype of girls and women with Turner syndrome is not X-imprinted. Hum Genet 121:469-74
Schmidt, Peter J; Cardoso, Graca M P; Ross, Judith L et al. (2006) Shyness, social anxiety, and impaired self-esteem in Turner syndrome and premature ovarian failure. JAMA 295:1374-6
Russell, Heather F; Wallis, Deeann; Mazzocco, Michele M M et al. (2006) Increased prevalence of ADHD in Turner syndrome with no evidence of imprinting effects. J Pediatr Psychol 31:945-55
Mazzocco, Michele M M; Thompson, Laurie; Sudhalter, Vicki et al. (2006) Language use in females with fragile X or Turner syndrome during brief initial social interactions. J Dev Behav Pediatr 27:319-28
Zinn, Andrew R; Ramos, Purita; Ross, Judith L (2006) A second recombination hotspot associated with SHOX deletions. Am J Hum Genet 78:523-5
Ross, Judith L; Kowal, Karen; Quigley, Charmian A et al. (2005) The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Leri-Weill dyschondrosteosis and Turner syndrome. J Pediatr 147:499-507

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