SNP genome scanning localizes oto-dental syndrome to chromosome 11q13 and microdeletions at this locus implicate FGF3 in dental and inner-ear disease and FADD in ocular coloboma
SNP genome scanning localizes oto-dental syndrome to chromosome 11q13 and microdeletions at this locus implicate FGF3 in dental and inner-ear disease and FADD in ocular coloboma
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DOI：
10.1093/hmg/ddm204
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发表时间：
2007-10-15
影响因子：
3.5
通讯作者：
Gregory-Evans, Kevin
中科院分区：
文献类型：
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作者：
Gregory-Evans, Cheryl Y.;Moosajee, Mariya;Gregory-Evans, Kevin
我们确定了三个不同的家庭受到耳牙综合征，一种罕见的，但严重的常染色体显性颅面畸形。所有受影响的患者都有明显增大的臼齿（globodontia）分离的高频感音神经性听力损失的独特表型。此外，眼缺损与疾病分离在一个家庭（眼-耳-牙综合征）。全基因组扫描使用Affyssin GeneChip 10 K 2.0阵列进行。参数连锁分析给出了单个LOD评分峰值3.9，确定与染色体11 q13的连锁。单倍型分析揭示了三个强制性重组事件，定义了D11 S1889和SNP rs 2077955之间的4.8 Mb连锁间隔。高分辨率定位和Southern印迹分析在每个家庭确定重叠半合子微缺失。患者淋巴母细胞系中的SNP表达分析和实时定量RT-PCR排除了对侧翼基因ORAOV 1、PPFIA 1和CTTN的位置效应。最小的43 kb缺失导致仅一个基因FGF 3的丢失，该基因在所有其他耳牙家族中也被缺失。这些数据表明，FGF 3单倍不足可能是耳牙综合征的原因。此外，Fas相关死亡结构域（FADD）基因也被删除在一个家庭分离眼缺损。斑马鱼胚胎时空原位杂交首次证实fadd在眼睛发育过程中表达。因此，我们建议，FADD单倍不足可能是负责眼缺损在这个家庭。因此，这项研究暗示FGF 3和FADD在人类颅面疾病。
We ascertained three different families affected with oto-dental syndrome, a rare but severe autosomal-dominant craniofacial anomaly. All affected patients had the unique phenotype of grossly enlarged molar teeth (globodontia) segregating with a high-frequency sensorineural hearing loss. In addition, ocular coloboma segregated with disease in one family (oculo-oto-dental syndrome). A genome-wide scan was performed using the Affymetrix GeneChip10K 2.0 Array. Parametric linkage analysis gave a single LOD score peak of 3.9 identifying linkage to chromosome 11q13. Haplotype analysis revealed three obligatory recombination events defining a 4.8 Mb linked interval between D11S1889 and SNP rs2077955. Higher resolution mapping and Southern blot analysis in each family identified overlapping hemizygous microdeletions. SNP expression analysis and real-time quantitative RT-PCR in patient lymphoblast cell lines excluded a positional effect on the flanking genes ORAOV1, PPFIA1 and CTTN. The smallest 43 kb deletion resulted in the loss of only one gene, FGF3, which was also deleted in all other otodental families. These data suggest that FGF3 haploinsufficiency is likely to be the cause of otodental syndrome. In addition, the Fas-associated death domain (FADD) gene was also deleted in the one family segregating ocular coloboma. Spatiotemporal in situ hybridization in zebrafish embryos established for the first time that fadd is expressed during eye development. We therefore propose that FADD haploinsufficiency is likely to be responsible for ocular coloboma in this family. This study therefore implicates FGF3 and FADD in human craniofacial disease.