Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Texas Children's Hospital, Houston, Texas, USA.
Am J Med Genet A. 2021 Mar;185(3):836-840. doi: 10.1002/ajmg.a.62066. Epub 2021 Jan 14.
Fibroblast growth factor receptor-like 1 (FGFRL1) encodes a transmembrane protein that is related to fibroblast growth factor receptors but lacks an intercellular tyrosine kinase domain. in vitro studies suggest that FGFRL1 inhibits cell proliferation and promotes cell differentiation and cell adhesion. Mice that lack FGFRL1 die shortly after birth from respiratory distress and have abnormally thin diaphragms whose muscular hypoplasia allows the liver to protrude into the thoracic cavity. Haploinsufficiency of FGFRL1 has been hypothesized to contribute to the development of congenital diaphragmatic hernia (CDH) associated with Wolf-Hirschhorn syndrome. However, data from both humans and mice suggest that disruption of one copy of FGFRL1 alone is insufficient to cause diaphragm defects. Here we report a female fetus with CDH whose 4p16.3 deletion allows us to refine the Wolf-Hirschhorn syndrome CDH critical region to an approximately 1.9 Mb region that contains FGFRL1. We also report a male infant with isolated left-sided diaphragm agenesis who carried compound heterozygous missense variants in FGFRL1. These cases provide additional evidence that deleterious FGFRL1 variants may contribute to the development of CDH in humans.
成纤维细胞生长因子受体样 1（FGFRL1）编码一种跨膜蛋白，与成纤维细胞生长因子受体相关，但缺乏细胞内酪氨酸激酶结构域。体外研究表明，FGFRL1 抑制细胞增殖，促进细胞分化和细胞黏附。缺乏 FGFRL1 的小鼠在出生后不久因呼吸窘迫而死亡，其膈肌异常薄，肌肉发育不良导致肝脏突入胸腔。推测 FGFRL1 的单倍不足可能导致与 Wolf-Hirschhorn 综合征相关的先天性膈疝（CDH）的发生。然而，来自人和小鼠的数据表明，单独破坏 FGFRL1 的一个拷贝不足以引起膈缺陷。在这里，我们报告了一例患有 CDH 的女性胎儿，其 4p16.3 缺失使我们能够将 Wolf-Hirschhorn 综合征 CDH 的关键区域精确定位到包含 FGFRL1 的约 1.9Mb 区域。我们还报告了一例患有孤立性左侧膈发育不全的男性婴儿，其 FGFRL1 存在复合杂合错义变异。这些病例提供了额外的证据表明，有害的 FGFRL1 变异可能导致人类 CDH 的发生。
