IDENTIFICATION OF RET GENE MUTATIONS IN INDIVIDUALS AT RISK FOR INHERITED MTC

眼指综合征(OD)是一种罕见的常染色体显性遗传 以发育和形态发生异常为特征的综合征 (如并指畸形、颅面畸形、牙釉质发育不良、 等等)，青光眼，以及缓慢进行性的痉挛瘫痪。我们有 利用GCRC的资源招募多个大家庭 并进行连锁分析，将S基因定位于 无序。到目前为止，我们已经确定了6个来自美国的大家庭 国家、加拿大和挪威，总共有47个可能 遗传信息性减数分裂(27名OD患者和20名OD患者 不受影响)。我已经为其中85%的人做过体检 以确认其表型。出现了一个观察结果 从这些分析中可以看出，畸形特征和/或 痉挛性截瘫的发病年龄似乎遵循这样的模式 被称为遗传预期的特征表达，也就是说， 遗传特征的表型严重程度和/或发病年龄较早 可能发生在连续的世代中。与已知的基因相比， 其他几种疾病与预期，这种表型遗传 模式提示存在三核苷酸重复扩增 导致这种疾病的基因。一篇报道这些观察结果的论文 发表在《美国医学遗传学杂志》上。 利用这些亲缘关系，我们已经开始了全基因组的搜索 短串联重复序列多态(STRP)标记与OD的连锁 疾病表型。在我们的初步结果中，基因组区域 包含HOX基因簇的第2、7、12和17号染色体被排除在外 作为所有家系的OD候选基因座。上个月，一家报纸报道 染色体6q22-q24(Hum Mol Genet)上OD基因的定位 6：123(97))。我们最近已经获得了这一标记的基因类型 我们家族的休息时间到了。我们已经确认了吸毒过量与此案的关联 在结合了我们亲缘关系的分析中，我们有 显著地进一步细化了染色体间隔，在该间隔中 耐受性基因一定是假的。我们目前正在刻画更多 多态标记基因类型以进一步缩小这一间隔，在 我们收集到的遗传物质以及在新的OD家庭中 被招募到这项研究。同时，我们正在测试 6q22-q24区域作为候选的扩展三联体重复序列 OD的基因突变。

Oculodentodigital syndrome (OD) is a rare autosomal dominantly inherited syndrome characterized by developmental and morphogenic abnormalities (e.g. syndactyly, craniofacial anomalies, dental enamel hypoplasia, etc.), glaucoma, and a slowly progressive spastic paraparesis. We have utilized the resources of the GCRC to recruit multiple large families with OD and to perform linkage analysis to map the gene(s) for the disorder. To date we have ascertained 6 large families from the United States, Canada, and Norway comprising a total of 47 potentially genetically informative meioses (27 individuals affected with OD and 20 unaffected). I have performed physical examinations on >85% of these individuals to confirm their phenotype. One observation which emerged from these analyses is that the severity of the dysmorphic traits and/or the age of onset of the spastic paraparesis appear to follow the pattern of trait expression known as genetic anticipation, that is, greater phenotypic severity and/or an earlier age of onset of inherited traits may occur in successive generations. Comparable to known genes for several other diseases with anticipation, this phenotypic inheritance pattern suggests the presence of a trinucleotide repeat expansion in the gene responsible for the disease. A paper reporting these observations is in press in the American Journal of Medical Genetics. Using these kindreds, we have embarked on a genome-wide search for linkage of short tandem repeat polymorphic (STRP) markers to the OD disease phenotype. In our initial results, genomic regions of chromosomes 2, 7, 12, and 17 containing HOX gene clusters were excluded as candidate loci for OD for all kindreds. Last month, a paper reported localization of a gene for OD to chromosome 6q22-q24 (Hum Mol Genet 6:123 (97)). We have recently obtained genotypes for markers in this interval for our kindreds. We have confirmed linkage of OD to this locus in an analysis which combines our kindreds, and we have significantly further refined the chromosomal interval in which a suceptibility gene must lie. We are currently characterizing more polymorphic marker genotypes to narrow this interval further, in the genetic material we have collected as well as in new OD families recruited to the study. Simultaneously, we are testing genes in the 6q22-q24 region for expanded triplet repeats as candidates for the genetic mutation underlying OD.