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

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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