Deletions in Xq26.3-q27.3 including FMR1 result in a severe phenotype in a male and variable phenotypes in females depending upon the X inactivation pattern
Deletions in Xq26.3-q27.3 including FMR1 result in a severe phenotype in a male and variable phenotypes in females depending upon the X inactivation pattern
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DOI：
10.1007/s004390050501
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发表时间：
1997-08-01
期刊：
影响因子：
5.3
通讯作者：
Willard, HF
中科院分区：
文献类型：
--
作者：
Wolff, DJ;Gustashaw, KM;Willard, HF
高分辨率细胞遗传学。微卫星标记分析和荧光原位杂交用于定义包含脆弱 X 基因 FMR1 的 Xq 缺失。在来自两个不相关家庭的个体中发现。在家庭 1 中，一名 19 岁男性的面部特征符合脆性 X 综合征；然而，他严重的智力和生长迟缓、睾丸小以及情人肢体骨骼缺陷和挛缩表现出更严重的表型，表明存在连续基因综合征。在先证者、他表型正常的母亲和他有学习障碍的非畸形妹妹中观察到包括 Xq26.3-q27.3 在内的细胞遗传学缺失。 FMR1 和雄激素受体位点的甲基化分析表明，删除的 X 在其母亲的白细胞中 > 95% 和姐姐的白细胞中，有 80-85% 处于失活状态。缺失的近端断点位于 FMR1 着丝粒约 10 Mb 处，远端断点位于 FMR1 远端 1 Mb 处。该缺失包含类似于 13 Mb 的 DMA，是迄今为止报道的包括 FMR1 在内的最大缺失。在第二个家族中，检测到了稍小的缺失。一名患有中度至重度精神发育迟滞、癫痫发作和甲状腺功能减退症的女性，其细胞遗传学从 Xq26.3 延伸到 q27.3，删除了 FMR1 基因周围大约 12 Mb 的 DNA。细胞遗传学和分子数据显示，她的白细胞中大约有 50% 含有活跃的删除 X。这些发现表明，具有包括 Xq26.3-q27.3 在内的删除的男性可能比典型的脆弱 X 男性表现出更严重的表型，而具有类似删除的女性可能会出现异常表型，如果删除的 X 在相当大比例的细胞中保持活跃。因此，除了 FMR1 之外，智力和神经发育的重要基因可能位于 Xq26.3-q27.3 中。该区域的一个候选基因 SOX3，被认为与神经元发育有关，它的缺失可能部分解释了我们患者更严重的表型。
High resolution cytogenetics. microsatellite marker analyses, and fluorescence in situ hybridization were used to define Xq deletions encompassing the fragile X gene, FMR1. detected in individuals from two unrelated families. In Family 1, a 19-year-old male had facial features consistent with fragile X syndrome; however, his profound mental and growth retardation, small testes, and lover limb skeletal defects and contractures demonstrated a more severe phenotype, suggestive of a contiguous gene syndrome. A cytogenetic deletion including Xq26.3-q27.3 was observed in the proband, his phenotypically normal mother, and his learning-disabled non-dysmorphic sister. Methylation analyses at the FMR1 and androgen receptor loci indicated that the deleted X was inactive in > 95% of his mother's white blood cells and 80-85% of the sister's leukocytes. The proximal breakpoint for the deletion was approximately 10 Mb centromeric to FMR1, and the distal breakpoint mapped 1 Mb distal to FMR1. This deletion, encompassing similar to 13 Mb of DMA, is the largest deletion including FMR1 reported to date. In the second family, a slightly smaller deletion was detected. A female with moderate to severe mental retardation, seizures, and hypothyroidism, had a de novo cytogenetic deletion extending from Xq26.3 to q27.3, which removed similar to 12 Mb of DNA around the FMR1 gene. Cytogenetic and molecular data revealed that similar to 50% of her white blood cells contained an active deleted X. These findings indicate that males with deletions including Xq26.3-q27.3 may exhibit a more severe phenotype than typical fragile X males, and females with similar deletions ma: have an abnormal phenotype if the deleted X remains active in a significant proportion of the cells. Thus, important genes for intellectual and neurological development, in addition to FMR1 may reside in Xq26.3-q27.3. One candidate gene in this region, SOX3, is thought to be involved in neuronal development and its loss may partly explain the more severe phenotypes of our patients.