TY - JOUR
T1 - Human sex reversal due to impaired nuclear localization of SRY
T2 - A clinical correlation
AU - Li, Biaoru
AU - Zhang, Wei
AU - Chan, Ging
AU - Jancso-Radek, Agnes
AU - Liu, Shunhe
AU - Weiss, Michael A.
PY - 2001/12/7
Y1 - 2001/12/7
N2 - SRY, an architectural transcription factor encoded by the sex-determining region of the Y chromosome, initiates testicular differentiation in mammalian embryogenesis. The protein contains a high-mobility group (HMG) box, a DNA-bending motif conserved among a broad class of nuclear proteins. Mutations causing human sex reversal (46, XY pure gonadal dysgenesis) are clustered in this domain. Basic N- and C-terminal regions of the HMG box are each proposed to provide nuclear localization signals. The significance of the C-terminal basic cluster (SRY residues 130-134) is uncertain, however, as its activity in cell culture varies with assay conditions. To test its importance, we have investigated a C-terminal sex-reversal mutation (R133W, position 78 of the HMG box). This de novo mutation impairs nuclear localization but not specific DNA binding or sharp DNA bending. Correlation between these properties and the phenotype of the patient suggests that nuclear localization of SRY is required for testicular differentiation and directed in part by the C-terminal basic cluster. To our knowledge, these results provide the first example of impaired organogenesis due to a nuclear localization signal mutation.
AB - SRY, an architectural transcription factor encoded by the sex-determining region of the Y chromosome, initiates testicular differentiation in mammalian embryogenesis. The protein contains a high-mobility group (HMG) box, a DNA-bending motif conserved among a broad class of nuclear proteins. Mutations causing human sex reversal (46, XY pure gonadal dysgenesis) are clustered in this domain. Basic N- and C-terminal regions of the HMG box are each proposed to provide nuclear localization signals. The significance of the C-terminal basic cluster (SRY residues 130-134) is uncertain, however, as its activity in cell culture varies with assay conditions. To test its importance, we have investigated a C-terminal sex-reversal mutation (R133W, position 78 of the HMG box). This de novo mutation impairs nuclear localization but not specific DNA binding or sharp DNA bending. Correlation between these properties and the phenotype of the patient suggests that nuclear localization of SRY is required for testicular differentiation and directed in part by the C-terminal basic cluster. To our knowledge, these results provide the first example of impaired organogenesis due to a nuclear localization signal mutation.
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U2 - 10.1074/jbc.C100388200
DO - 10.1074/jbc.C100388200
M3 - Article
C2 - 11641389
AN - SCOPUS:0035824513
SN - 0021-9258
VL - 276
SP - 46480
EP - 46484
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 49
ER -