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The elucidation of pathoenic mechanism of cranio-maxillo-facial anomdy and the applicaton for gene diagnosis

颅颌面畸形发病机制的阐明及其在基因诊断中的应用

基本信息

批准号：
13672081
负责人：
MOTI Yoshiyuki
金额：
$ 1.66万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672081/
关键词：
gene mutation FGFRS craniosynostosis cleidoranial dysplasia CBFAI Homeobox 口唇裂口唇口蓋裂 MSXI DLX2

项目摘要

The purpose of this study is to systematically analysis for candidate gene of a series of congenital morphological anomaly.Craniosynostosis is the pathologic condition that results from premature fusion of one or more cranial sutures. Recently, mutations of the fibroblast growth factor receptor (FGFR) genes have been detected in syndromic craniosynostosis. The fibroblast growth factor(FGF) and FGFR regulate multiple cellular activities, cell growth and embryonal development. Firstly, we examined nucleotide sequences of FGFR2 in Japanese craniosynostosis patients (Crouzon syndrome : 9 cases, Apert syndrome : 6 cases and scaphocephaly : 3 cases as non-syndromic patients) by polymerase chain reaction (PCR) followed by direct sequencing methods. The results demonstrated FGFR2 heterozygous mutations at codons 252, 290 of exon 7, and at codon 342, 354 of exon 9 in Crouzon syndromes, in Apert syndrome patients, Ser252Trp and Pro253Arg were detected in five and one patients, respectively. No m … More utation was detected in one case of Crouzon, all cases of scaphocephaly and healthy individuals. Thus far sequence analysis of FGFR2 in syndromic craniosynostosis has been reported in many Caucasian patients, whereas in Japanese only several cases have been studied. The present study with IS patients confirmed mat a similar series of mutations occur in Japanese patients as in Caucasian patients regardless of ethnicity and environment. The frequency of the mutation was 82% (9/11 cases) in Japanese Crouzon patients. The ratio of S252W : P253R was 5 : 1 in Japanese Apert patients. Morever, in Japanese Apert patients, complication rate of cleft palate was 60% for mutation of Ser252Trp and 0/2 of patients for Pro253Arg, with their syndactyly score being 4.90 and 5.50, respectively.Homeobox (HOX) gene has the role which is important for the morphogenesis in the embryonic stage. Secondary, hand anomaly of Apert syndrome was suspected as cause of HOXA13 and HOXD13 gene, so we analyzed them. Moreover, we also analyzed MSX1(HOX7) gene as cause of cleft palate in Apert syndrome. We detected several polymorphism and mere were possibility of different frequency between Apert group and healthy control group.Next subject, cleidocranial dysplasia (CCD) is an autosomal dominant human bone disease characterized by hypoplastic or aplastic clavicles, wide cranial sutures, supernumerary teeth, short stature, and other skeletal disorders. Recently, various mutations of the core binding factor (CBFAI) gene have been detected in CCD patients. The CBFAI gene is a member of the runt family of transcription factors. We experienced one Japanese case of CCD with open sutures, hypoplasia of clavicles and brachydactyly, combined with atlant-axis dislocation. We performed the sequence analysis of the CBFAI gene and detected a missense mutation of R225W in exon 3. Less

本研究的目的是系统地分析一系列先天性形态异常的候选基因。颅缝早闭是由于一条或多条颅缝过早融合而导致的病理状态。最近，成纤维细胞生长因子受体（FGFR）基因突变已被检测到综合征颅缝早闭。成纤维细胞生长因子（FGF）和FGFR调节多种细胞活动，细胞生长和胚胎发育。首先，我们研究了日本颅缝早闭患者（Crouzon综合征：9例，Apert综合征：6例和舟状头畸形：3例非综合征患者）的FGFR 2的核苷酸序列，通过聚合酶链反应（PCR），然后直接测序方法。结果表明，Crouzon综合征患者FGFR 2基因第7外显子第252、290位密码子和第9外显子第342、354位密码子存在杂合突变，Apert综合征患者中分别有5例和1例检测到Ser 252 Trp和Pro253 Arg杂合突变。没有m ...更多信息 1例Crouzon、所有舟状头畸形和健康人均检测到突变。到目前为止，在许多高加索患者中已经报道了综合征型颅缝早闭中FGFR 2的序列分析，而在日本仅研究了几个病例。目前对IS患者的研究证实，日本患者与高加索患者发生了类似的一系列突变，无论种族和环境如何。在日本Crouzon患者中，突变频率为82%（9/11例）。日本Apert患者S252 W：P253 R的比值为5：1。此外，日本Apert患者中Ser 252 Trp突变的腭裂并发症发生率为60%，Pro253 Arg突变的腭裂并发症发生率为0/2，并指评分分别为4.90和5.50，HOX基因在胚胎期的形态发生中起重要作用。其次，Apert综合征的手畸形被怀疑是HOXA 13和HOXD 13基因的原因，因此我们分析了它们。此外，我们还分析了MSX 1（HOX 7）基因作为Apert综合征腭裂的病因。我们检测了Apert组和健康对照组之间的几个多态性和可能的不同频率。下一个主题，锁骨颅发育不良（cleidocranial dysplasia，CCD）是一种常染色体显性遗传的人类骨疾病，其特征是锁骨发育不全或再生障碍，宽颅缝，多生牙，身材矮小和其他骨骼疾病。最近，在CCD患者中检测到核心结合因子（CBFAI）基因的各种突变。CBFAI基因是转录因子的runt家族的成员。我们经历了一例日本CCD病例，伴有开放性缝合、锁骨发育不全和短指畸形，合并寰枢椎脱位。我们进行了CBFAI基因的序列分析，并检测到R225 W的错义突变的外显子3。少