The clinical impact of chromosomal rearrangements with breakpoints upstream of the SOX9 gene: two novel de novo balanced translocations associated with acampomelic campomelic dysplasia.
The clinical impact of chromosomal rearrangements with breakpoints upstream of the SOX9 gene: two novel de novo balanced translocations associated with acampomelic campomelic dysplasia.
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DOI：
10.1186/1471-2350-14-50
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发表时间：
2013-05-07
影响因子：
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通讯作者：
Vianna-Morgante AM
中科院分区：
文献类型：
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作者：
Fonseca AC;Bonaldi A;Bertola DR;Kim CA;Otto PA;Vianna-Morgante AM
与SOX9 [SRY（性别决定区Y）-框9]附近的断点平衡重排与骨骼异常的关联已被归因于通过直接破坏调控元件、其与SOX9的分离或并列序列的作用而推定改变SOX9表达。我们报告两个散发的明显平衡易位，t（7; 17）（p13; q24）和t（17; 20）（q24.3; q11.2），其携带者有骨骼异常，导致诊断为acampomelic campomelic发育不良（ACD; MIM 114290）。通过a-CGH未检测到致病性染色体不平衡。将17号染色体断裂点分别定位在SOX 9基因上游917 - 855 kb和601 - 585 kb处。与SOX 9相关的骨骼疾病相关的17号染色体上的平衡重排断点的远端簇已被映射到SOX 9上游932 - 789 kb的片段。在该簇中，本文所述的t（17; 20）的断裂点对于SOX 9是最端粒的，因此允许将与骨骼疾病相关的远端断裂点簇区域的端粒边界重新定义为SOX 9上游的601 - 585 kb。尽管两例患者都有骨骼异常，但t（7; 17）携带者表现出相对较轻的临床特征，而t（17; 20）在一名患有严重支气管软化症的男孩中检测到，这取决于机械通气。与性别决定障碍相关的平衡和不平衡重排导致将SOX 9功能对睾丸分化的调节区域映射到SOX 9上游的517 - 595 kb间隔，以及TESCO（SOX 9核心的睾丸特异性增强子）。由于t（17; 20）携带者具有XY性染色体结构和正常的男性发育，因此易位断裂点远端的17号染色体片段应包含正常睾丸发育的调控元件。这两种新的易位说明了在SOX 9附近具有断点的平衡易位携带者的临床变异性。易位t（17; 20）断裂点提供了在SOX 9基因上游517至595 kb处存在另外的睾丸特异性SOX 9增强子的进一步证据。
The association of balanced rearrangements with breakpoints near SOX9 [SRY (sex determining region Y)-box 9] with skeletal abnormalities has been ascribed to the presumptive altering of SOX9 expression by the direct disruption of regulatory elements, their separation from SOX9 or the effect of juxtaposed sequences. We report on two sporadic apparently balanced translocations, t(7;17)(p13;q24) and t(17;20)(q24.3;q11.2), whose carriers have skeletal abnormalities that led to the diagnosis of acampomelic campomelic dysplasia (ACD; MIM 114290). No pathogenic chromosomal imbalances were detected by a-CGH. The chromosome 17 breakpoints were mapped, respectively, 917–855 kb and 601–585 kb upstream of the SOX9 gene. A distal cluster of balanced rearrangements breakpoints on chromosome 17 associated with SOX9-related skeletal disorders has been mapped to a segment 932–789 kb upstream of SOX9. In this cluster, the breakpoint of the herein described t(17;20) is the most telomeric to SOX9, thus allowing the redefining of the telomeric boundary of the distal breakpoint cluster region related to skeletal disorders to 601–585 kb upstream of SOX9. Although both patients have skeletal abnormalities, the t(7;17) carrier presents with relatively mild clinical features, whereas the t(17;20) was detected in a boy with severe broncheomalacia, depending on mechanical ventilation. Balanced and unbalanced rearrangements associated with disorders of sex determination led to the mapping of a regulatory region of SOX9 function on testicular differentiation to a 517–595 kb interval upstream of SOX9, in addition to TESCO (Testis-specific enhancer of SOX9 core). As the carrier of t(17;20) has an XY sex-chromosome constitution and normal male development for his age, the segment of chromosome 17 distal to the translocation breakpoint should contain the regulatory elements for normal testis development. These two novel translocations illustrate the clinical variability in carriers of balanced translocations with breakpoints near SOX9. The translocation t(17;20) breakpoint provides further evidence for an additional testis-specific SOX9 enhancer 517 to 595 kb upstream of the SOX9 gene.