Bad bones, absent smell, selfish testes: The pleiotropic consequences of human FGF receptor mutations

Abstract

The discovery in 1994 that highly specific mutations of fibroblast growth factor (FGF) receptor 3 caused the most common form of human short-limbed dwarfism, achondroplasia, heralded a new era in FGF receptor (FGFR) biology. A decade later, the purpose of this review is to survey how the study of humans with FGFR mutations continues to provide insights into FGFR function in health and disease, and the clinical applications of these findings. Amongst the most interesting recent discoveries have been the description of novel phenotypes associated with FGFR1 and FGFR3 mutations; identification of fundamental differences in the cellular mechanisms of mutant FGFR2 and FGFR3 action; and the direct identification of FGFR2 and FGFR3 mutations in sperm. These clinical observations illustrate the pleiotropism of FGFR action and fuel ongoing efforts to understand the rich biology and pathophysiology of the FGF signalling system.

Introduction

In 1994, two groups independently described the identification of specific heterozygous nucleotide substitutions (1138G > A or C, both encoding Gly380Arg) of the FGFR3 gene in 39 unrelated individuals with achondroplasia, accounting for all cases studied [1], [2]. This remarkable discovery presaged a burst of activity that led to the identification of germline mutations in the FGFR1 and FGFR2 genes within just a few months [3], [4], [5]. Striking parallels in the early findings between the different fibroblast growth factor receptors (FGFRs) heralded several emergent themes that have continued to dominate the agenda of human genetics research in this field. The mutations identified were dominantly acting, encoded a relatively limited repertoire of specific missense substitutions that caused congenital skeletal abnormalities (either short-limbed bone dysplasia or craniosynostosis, the premature fusion of the cranial sutures), and many occurred recurrently with remarkably high rates of new mutation. It soon became apparent, at least for FGFR2 and FGFR3, that different mutations within each gene were associated with distinct phenotypes, constituting allelic series [6], [7]. This in turn implied quantitative or qualitative differences in the function of mutant proteins, spawning efforts to study these differences using biochemical and mouse genetic approaches. Subsequent human genetic discoveries of particular importance have been the description of a common, hitherto unrecognised craniosynostosis syndrome caused by a specific FGFR3 P250R mutation [8], [9] and the more recent findings that haploinsufficiency and constitutive gain-of-function mutations of FGFR1, and a putative dominant negative mutation of FGFR3, cause strikingly different phenotypes from those associated with the earlier described mutations [10], [11], [12].

Another challenge has been to explain the very high rates of specific FGFR mutations, some of which appear elevated ∼500-fold above background levels. Several of the most frequent mutations have been shown to originate exclusively from the unaffected father and are associated with increased paternal age, relative to the population average, at the time of conception. These observations have led to efforts to identify these specific mutations in sperm, which have recently been successful [13], [14], [15]. Evidence for the paradoxical selective advantage of an FGFR2 mutation in the testis [14] provides an unexpected example of the pleiotropism of mutant FGFR action.

Many reviews on different aspects of the human genetics of FGFR mutation have been published [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. Approaches such as biochemical dissection and structural analysis are addressed elsewhere in this issue [26], [27], [28]. The scope of this article will be to collate and update information gleaned from the clinical study of humans with germline FGFR mutations, focusing particularly on discoveries of the past five years. Somatically arising FGFR mutations associated with cancer are reviewed in an accompanying article [29].