Challa Pratap, Hauser Michael Arthur, Luna Coralia Catalina, Freedman Sharon Fridovich, Pericak-Vance Margaret, Yang Jun, McDonald Marie Theresa, Allingham R Rand
Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA.
Mol Vis. 2006 Aug 28;12:1009-15.
To describe the clinical, ocular, and genetic findings in multiple members of a family with early-onset and bilateral lens dislocation, clinical corneal guttae, and glaucoma.
All family members underwent complete physical and ophthalmic examinations. After informed consent was given, DNA was obtained from eleven family members, eight of whom were affected. Three polymorphic markers near the fibrillin 1 (FBN1) locus were genotyped and the results analyzed using the VITESSE program. Amplification of the 65 exons and flanking intronic sequences of FBN1 was performed using polymerase chain reaction (PCR), followed by conformation sensitive gel electrophoresis (CSGE). Then, all fragments with mobility variations were sequenced.
Pedigree analysis revealed a three generation family with eight of eleven individuals affected by early onset lens dislocation, high myopia, typical facies, frontal bossing, flexion contractures, proximal interphalangeal (PIP) joint thickening, clinical corneal guttae, and glaucoma. Genetic linkage analysis using polymorphic markers near FBN1 demonstrated an LOD score of 1.78 (maximum possible LOD score 1.78). Conformation sequence gel electrophoresis analysis suggested a sequence variation in exon 3. Sequencing revealed a C965G substitution, resulting in an S322C coding change. This sequence variant segregated with affection status and was not identified in 154 control chromosomes.
This syndrome is consistent with a novel mutation in the FBN1 gene. FBN1 mutations have been previously described as causative for Marfan syndrome. The early-onset of complete lens dislocation, progressive corneal guttae, and glaucoma is unusual for Marfan syndrome. This study expands the Marfan phenotype and demonstrates a possible link between guttae, glaucoma, and fibrillin 1 disorders.
描述一个患有早发性双侧晶状体脱位、临床角膜小滴和青光眼的家族中多名成员的临床、眼部和基因学发现。
所有家族成员均接受了全面的体格和眼科检查。在获得知情同意后，从11名家族成员中获取了DNA，其中8人患病。对原纤维蛋白1（FBN1）基因座附近的三个多态性标记进行基因分型，并使用VITESSE程序分析结果。使用聚合酶链反应（PCR）扩增FBN1的65个外显子和侧翼内含子序列，随后进行构象敏感凝胶电泳（CSGE）。然后，对所有迁移率有变化的片段进行测序。
系谱分析显示这是一个三代家族，11名个体中有8人患有早发性晶状体脱位、高度近视、典型面容、额部隆起、屈曲挛缩、近端指间（PIP）关节增厚、临床角膜小滴和青光眼。使用FBN1附近的多态性标记进行基因连锁分析显示LOD值为1.78（最大可能LOD值为1.78）。构象序列凝胶电泳分析提示外显子3存在序列变异。测序显示有一个C965G替换，导致编码改变为S322C。该序列变异与患病状态相关，在154条对照染色体中未发现。
该综合征与FBN1基因的一个新突变一致。FBN1突变先前已被描述为马凡综合征的病因。完全性晶状体脱位的早发、进行性角膜小滴和青光眼在马凡综合征中并不常见。本研究扩展了马凡综合征的表型，并证明了角膜小滴、青光眼和原纤维蛋白1疾病之间可能存在联系。
