Molecular Analysis of Genes on Xp Controlling Turner Syndrome
Molecular Analysis of Genes on Xp Controlling Turner Syndrome
Monosomy X has been known to be the chromosomal basis of Turner syndrome (TS) for more than four decades. A large body of cytogenetic data indicates that most TS features are due to reduced dosage of genes on the short arm of the X chromosome (Xp). Phenotype mapping studies using molecular cytogenetic and genetic techniques are beginning to localize the Xp genes that are important for various TS features, and a comprehensive catalog of candidate genes is becoming available through the Human Genome Project and related research. It is now possible to assess the contributions of individual genes to the TS phenotype by mutational analysis of karyotypically normal persons with specific TS features. This strategy has succeeded in identifying a gene involved in short stature and is being applied to premature ovarian failure and other TS phenotypes.
Turner syndrome (TS) is the phenotype of human females with complete or partial monosomy X. 1 TS females classically manifest short stature, webbed neck, increased carrying angle of the elbow (cubitus valgus), and gonadal failure. 2 More recently, other physical anomalies such as aortic coarctation 3 as well as selective cognitive deficits in nonverbal domains such as visual-spatial abilities 4,5 have been described.
A variety of karyotypes, including 45,X (complete monosomy X), 46,X,i(Xq) (isochromosome for the long arm), 46,X,del(X) (partial X deletion), 46,X,r(X) (ring X), and others, are associated with TS, with a combined incidence of about 1 in 2000 live born girls. These abnormal chromosomal constitutions have in common a single copy of all or part of the X chromosome, implying that most TS features are the result of reduced dosage of X-linked genes. As with many human developmental disorders, the pathophysiology of these features is poorly understood, and it is hoped that identifying specific genes responsible for TS abnormalities will shed light on their underlying mechanisms. This article reviews our knowledge of the specific genes on the short arm of the X chromosome that may contribute to TS (Fig. 1).
(Enlarge Image)
Map of X chromosome short arm showing critical regions, associated TS phenotypes, and candidate genes.
With the possible exception of genes for premature ovarian failure (POF), TS genes are predicted to escape X inactivation, so that they are reduced in dosage (haploinsufficient) in 45,X cells relative to 46,XX cells. Ovarian genes do not necessarily escape inactivation because the inactive X chromosome is reactivated in oocytes prior to the onset of meiosis. A second prediction for TS genes, excluding those involved in sexlimited traits, is the presence of Y-linked homologs; otherwise, normal 46,XY males would be haploinsuffcient. To sum, somatic TS genes are predicted to escape X inactivation and to have functionally equivalent X and Y homologs.
The TS phenotype is highly variable, with some degree of growth failure being the only universal finding. One reason for this variability is genetic heterogeneity, for example, the different karyotypes already mentioned. This phenotypic and genetic variability enables cytogeneticists to make karyotype-phenotype correlations. Such studies indicate that genes for physical and cognitive features lie on Xp, whereas genes for ovarian function are present on both Xp and Xq. Most efforts to map specific TS traits have been directed toward Xp.
One such mapping effort was our study in which we compared the phenotypes of 29 subjects missing different portions of Xp. We found statistically significant evidence for loci in Xp11.2-p22.1 influencing height (adjusted for midparental height) and ovarian failure. We also found suggestive evidence for genes in the same interval involved in high arched palate and autoimmune thyroid disease. With an increase in sample size to n = 42 subjects, the associations of POF and adjusted height phenotypes with deletions of this Xp interval remain statistically significant (Fig. 2).
(Enlarge Image)
Association of deleted Xp markers and premature ovarian failure (POF) or adjusted height standard deviation score in 42 females with partial Xp deletions. Dashed line shows threshold for statistical significance.
Studies by others have shown that another region of Xp, the pseudoautosomal region (PAR1), contains a locus that influences stature. The sex chromosomes pair and recombine in PAR1 during male meiosis, maintaining nucleotide sequence identity between the X and Y copies, and PAR1 genes all appear to escape X inactivation. The molecular properties of PAR1 thus make it a logical site for TS genes, and recently we found evidence that deletions of PAR1 are also associated with TS neurocognitive deficits. However, other data strongly suggest that genes outside PAR1 must also play a role in TS.
Monosomy X has been known to be the chromosomal basis of Turner syndrome (TS) for more than four decades. A large body of cytogenetic data indicates that most TS features are due to reduced dosage of genes on the short arm of the X chromosome (Xp). Phenotype mapping studies using molecular cytogenetic and genetic techniques are beginning to localize the Xp genes that are important for various TS features, and a comprehensive catalog of candidate genes is becoming available through the Human Genome Project and related research. It is now possible to assess the contributions of individual genes to the TS phenotype by mutational analysis of karyotypically normal persons with specific TS features. This strategy has succeeded in identifying a gene involved in short stature and is being applied to premature ovarian failure and other TS phenotypes.
Turner syndrome (TS) is the phenotype of human females with complete or partial monosomy X. 1 TS females classically manifest short stature, webbed neck, increased carrying angle of the elbow (cubitus valgus), and gonadal failure. 2 More recently, other physical anomalies such as aortic coarctation 3 as well as selective cognitive deficits in nonverbal domains such as visual-spatial abilities 4,5 have been described.
A variety of karyotypes, including 45,X (complete monosomy X), 46,X,i(Xq) (isochromosome for the long arm), 46,X,del(X) (partial X deletion), 46,X,r(X) (ring X), and others, are associated with TS, with a combined incidence of about 1 in 2000 live born girls. These abnormal chromosomal constitutions have in common a single copy of all or part of the X chromosome, implying that most TS features are the result of reduced dosage of X-linked genes. As with many human developmental disorders, the pathophysiology of these features is poorly understood, and it is hoped that identifying specific genes responsible for TS abnormalities will shed light on their underlying mechanisms. This article reviews our knowledge of the specific genes on the short arm of the X chromosome that may contribute to TS (Fig. 1).
(Enlarge Image)
Map of X chromosome short arm showing critical regions, associated TS phenotypes, and candidate genes.
With the possible exception of genes for premature ovarian failure (POF), TS genes are predicted to escape X inactivation, so that they are reduced in dosage (haploinsufficient) in 45,X cells relative to 46,XX cells. Ovarian genes do not necessarily escape inactivation because the inactive X chromosome is reactivated in oocytes prior to the onset of meiosis. A second prediction for TS genes, excluding those involved in sexlimited traits, is the presence of Y-linked homologs; otherwise, normal 46,XY males would be haploinsuffcient. To sum, somatic TS genes are predicted to escape X inactivation and to have functionally equivalent X and Y homologs.
The TS phenotype is highly variable, with some degree of growth failure being the only universal finding. One reason for this variability is genetic heterogeneity, for example, the different karyotypes already mentioned. This phenotypic and genetic variability enables cytogeneticists to make karyotype-phenotype correlations. Such studies indicate that genes for physical and cognitive features lie on Xp, whereas genes for ovarian function are present on both Xp and Xq. Most efforts to map specific TS traits have been directed toward Xp.
One such mapping effort was our study in which we compared the phenotypes of 29 subjects missing different portions of Xp. We found statistically significant evidence for loci in Xp11.2-p22.1 influencing height (adjusted for midparental height) and ovarian failure. We also found suggestive evidence for genes in the same interval involved in high arched palate and autoimmune thyroid disease. With an increase in sample size to n = 42 subjects, the associations of POF and adjusted height phenotypes with deletions of this Xp interval remain statistically significant (Fig. 2).
(Enlarge Image)
Association of deleted Xp markers and premature ovarian failure (POF) or adjusted height standard deviation score in 42 females with partial Xp deletions. Dashed line shows threshold for statistical significance.
Studies by others have shown that another region of Xp, the pseudoautosomal region (PAR1), contains a locus that influences stature. The sex chromosomes pair and recombine in PAR1 during male meiosis, maintaining nucleotide sequence identity between the X and Y copies, and PAR1 genes all appear to escape X inactivation. The molecular properties of PAR1 thus make it a logical site for TS genes, and recently we found evidence that deletions of PAR1 are also associated with TS neurocognitive deficits. However, other data strongly suggest that genes outside PAR1 must also play a role in TS.
