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

本研究的目的是系统分析一系列先天性形态异常的候选基因。颅缝融合是指一条或多条颅缝过早融合所致的病理状态。最近，在综合征颅缝融合症中发现了成纤维细胞生长因子受体(FGFR)基因突变。成纤维细胞生长因子(成纤维细胞生长因子)和成纤维细胞生长因子受体调节多种细胞活动、细胞生长和胚胎发育。本研究首先采用聚合酶链式反应(PCR)和直接测序的方法，检测了日本颅性融合畸形患者(Crouzon综合征9例，Apert综合征6例，肩头畸形3例)FGFR2基因的核苷酸序列。Crouzon综合征患者外显子7密码子252、290、外显子9密码子342、354发生FGFR2杂合性突变，Apert综合征患者Ser252Trp、Pro253Arg分别检出5例和1例。不是m…在一个Crouzon病例、所有肩头畸形病例和健康个体中发现了更多的突起。到目前为止，在许多高加索患者中已经报道了FGFR2在综合征颅缝融合症中的序列分析，而在日本只有几个病例被研究过。目前对IS患者的研究证实，无论种族和环境如何，日本患者与高加索患者都会发生类似的一系列突变。日本Crouzon患者中该突变频率为82%(9/11例)。日本Apert患者S252W/P253R的比例为5：1。此外，在日本Apert患者中，Ser252Trp突变和Pro253Arg突变的腭裂并发症发生率分别为60%和0/2，并指得分分别为4.90和5.50。同源框(Homeobox，HOX)基因在胚胎期的形态发生中起重要作用。其次，Apert综合征的手部异常被怀疑为HOXA13和Hoxd13基因的原因，因此我们对其进行了分析。此外，我们还分析了Msx1(HOX7)基因与Apert综合征腭裂的关系。我们检测了Apert组和健康对照组之间的几个基因多态性和可能的不同频率。下一个研究对象，锁骨颅骨发育不良症是一种常染色体显性遗传性人类骨病，其特征是锁骨发育不良或再生障碍性疾病，宽大的颅缝，多馀的牙齿，矮小的身材和其他骨骼疾病。最近，核心结合因子(CBFAI)基因的各种突变被检测到存在于CCD患者中。CBFAI基因是矮小转录因子家族的成员。我们经历了一个日本的病例，有开放的缝线，锁骨发育不良和短指，合并枢椎脱位。我们对CBFAI基因进行了序列分析，并在外显子3检测到了R225W的错义突变。

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