Lansdon L A, Bernabe H V, Nidey N, Standley J, Schnieders M J, Murray J C
1 Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
2 Department of Biology, University of Iowa, Iowa City, IA, USA.
J Dent Res. 2017 Oct;96(11):1339-1345. doi: 10.1177/0022034517726496. Epub 2017 Aug 21.
Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 ( FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies. The proband presented with bilateral cleft lip and palate, malformed auricles, and bilateral ectrodactyly of his hands and feet at birth. He was later diagnosed with diabetes insipidus, spastic quadriplegia, developmental delay, agenesis of the corpus callosum, and enlargement of the third cerebral ventricle. We noted the substantial phenotypic overlap with individuals with Hartsfield syndrome, the rare combination of holoprosencephaly and ectrodactyly. Sequencing of FGFR1 identified a previously unreported de novo variant in exon 11 (p.Gly487Cys), which we modeled to determine its predicted effect on the protein structure. Although it was not predicted to significantly alter protein folding stability, it is possible this variant leads to the formation of nonnative intra- or intermolecular disulfide bonds. We then mapped this and other disease-associated variants to a 3-dimensional model of FGFR1 to assess which protein domains harbored the highest number of pathogenic changes. We observed the greatest number of variants within the domains involved in FGF binding and FGFR activation. To further explore the contribution of each variant to disease, we recorded the phenotype resulting from each FGFR1 variant to generate a series of phenotype-specific protein maps and compared our results to benign variants appearing in control databases. It is our hope that the use of phenotypic maps such as these will further the understanding of genetic disease in general and diseases caused by variation in FGFR1 specifically.
在此，我们描述了由成纤维细胞生长因子受体1（FGFR1）变体引起的疾病的基因型-表型相关性，并报告了一名患有多种先天性异常的个体中FGFR1的一种新的、从头出现的变体。先证者出生时表现为双侧唇腭裂、耳廓畸形以及双手和双脚双侧缺指（趾）畸形。他后来被诊断患有尿崩症、痉挛性四肢瘫痪、发育迟缓、胼胝体发育不全以及第三脑室扩大。我们注意到该个体与患有哈茨菲尔德综合征（全前脑畸形和缺指（趾）畸形的罕见组合）的个体在表型上有大量重叠。对FGFR1进行测序后，在第11外显子中发现了一个先前未报道的从头出现的变体（p.Gly487Cys），我们对其进行建模以确定其对蛋白质结构的预测影响。尽管预计它不会显著改变蛋白质折叠稳定性，但这种变体有可能导致形成非天然的分子内或分子间二硫键。然后，我们将此变体及其他与疾病相关的变体映射到FGFR1的三维模型上，以评估哪些蛋白质结构域含有最多的致病性变化。我们观察到在参与FGF结合和FGFR激活的结构域中变体数量最多。为了进一步探究每个变体对疾病的影响，我们记录了每个FGFR1变体所导致的表型，以生成一系列特定表型的蛋白质图谱，并将我们的结果与对照数据库中出现的良性变体进行比较。我们希望使用这样的表型图谱能够进一步加深对一般遗传疾病，特别是由FGFR1变异引起的疾病的理解。
