TY - JOUR
T1 - Position effects due to chromosome breakpoints that map ∼900 Kb upstream and ∼1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia
AU - Velagaleti, Gopalrao V.N.
AU - Bien-Willner, Gabriel A.
AU - Northup, Jill K.
AU - Lockhart, Lillian H.
AU - Hawkins, Judy C.
AU - Jalal, Syed M.
AU - Withers, Marjorie
AU - Lupski, James R.
AU - Stankiewicz, Pawel
N1 - Funding Information:
We thank the patients and their families for their participation in this study. We appreciate the critical reviews of Drs. Veronica van Heyningen, Dirk-Jan Kleinjan, Brendan Lee, and Gerd Scherer. We thank Dr. Weimin Bi, for helpful discussion; Dr. Chad Shaw, for assistance with the statistical analyses; Dr. Marjorie R. Grafe, for the autopsy notes and pictures; and Dr. Svetlana A. Yatsenko and Charles Zaremba, for technical assistance. This work was generously supported by grants from the National Institute of Child Health and Human Development (PO1 HD39420) and the Baylor College of Medicine Mental Retardation Research Center (HD24064).
PY - 2005/4
Y1 - 2005/4
N2 - Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y-related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25. 1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1:: 7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.
AB - Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y-related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25. 1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1:: 7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.
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U2 - 10.1086/429252
DO - 10.1086/429252
M3 - Article
C2 - 15726498
AN - SCOPUS:15944402131
SN - 0002-9297
VL - 76
SP - 652
EP - 662
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -