Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2
Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2
复制标题
FGFR2 IgII-IgIII 连接子中核苷酸取代的基因型-表型相关性
DOI：
10.1093/hmg/6.1.137
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发表时间：
1997-01-01
影响因子：
3.5
通讯作者：
Wilkie, AOM
中科院分区：
文献类型：
--
作者：
Oldridge, M;Lunt, PW;Wilkie, AOM
纤维细胞生长因子受体2 （FGFR2）基因的显性等位基因突变已在五种颅缝闭锁综合征中被描述，在以手和脚并指为特征的Apert综合征中，在IgII和IgIII细胞外免疫球蛋白样结构域之间的连接物中，丝氨酸-脯氨酸二肽（Ser252Trp或Pro253Arg）的复发性突变已在160多个无关个体中被记录。我们已经确定了这种二肽的三个新的突变，与不同的表型相关。在一名患有轻度Crouzon综合征（四肢正常的颅缝闭闭）的男孩身上发现的预测Ser252Leu替代的C- >T突变也存在于他的三个临床正常家庭成员身上，预测Ser252Phe替代的CG- >TT突变导致与Apert综合征一致的表型，最后，预测双氨基酸替代（Ser252Phe和Pro253Ser）的CGC- >TCT突变导致Pfeiffer综合征变异，伴有轻度颅缝闭闭。大拇指和大脚趾，数指固定延伸，仅有少量皮肤并指。观察到Ser252Phe突变导致Apert综合征，而其他单或双替换与较轻或正常表型相关，这突出了与Apert综合征相关的肢体和颅面异常的精细特异性分子发病机制。Ser252Phe是在这种疾病中发现的第一个非典型突变，其罕见性可以解释为丝氨酸密码子的两个残基需要突变。对涉及相同核苷酸的独立复杂核苷酸取代的描述是前所未有的，我们推测这可能是精子中FGFR突变的功能选择的结果。
Dominantly acting, allelic mutations of the fibroblast growth factor receptor 2 (FGFR2) gene have been described in five craniosynostosis syndromes, In Apert syndrome, characterised by syndactyly of the hands and feet, recurrent mutations of a serine-proline dipeptide (either Ser252Trp or Pro253Arg) in the linker between the IgII and IgIII extracellular immunoglobulin-like domains, have been documented in more than 160 unrelated individuals. We have identified three novel mutations of this dipeptide, associated with distinct phenotypes. A C-->T mutation that predicts a Ser252Leu substitution, ascertained in a boy with mild Crouzon syndrome (craniosynostosis with normal limbs) is also present in three clinically normal members of his family, A CG-->TT mutation that predicts a Ser252Phe substitution results in a phenotype consistent with Apert syndrome, Finally, a CGC-->TCT mutation that predicts a double amino acid substitution (Ser252Phe and Pro253Ser) causes a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the Ser252Phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlights the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. Ser252Phe is the first noncanonical mutation to be identified in this disorder, its rarity being explained by the requirement for two residues of the serine codon to be mutated. The description of independent, complex nucleotide substitutions involving identical nucleotides is unprecedented, and we speculate that this may result from functional selection of FGFR mutations in sperm.