Читать книгу Pathology of Genetically Engineered and Other Mutant Mice - Группа авторов - Страница 110

Cilia are incredibly complex organelles whose biogenesis and functions involve the interactions of many different genes (multigenicity). As a result, ciliopathies are phenotypically and genetically heterogeneous. Mutations involving a single gene can produce very different phenotypes depending on genetic background which introduces the varying effects of gene modifiers, gene redundancy, and allelism [15]. The modifier roles of specific alleles [96, 97] and multi‐protein modules further illustrate the complexity of interactions between ciliary proteins [98].

For example, in both human and mouse PKD, genetic background effects modulate the renal and extrarenal phenotypes [99, 100]. For example, Tmem67^bpck mice show a less severe kidney phenotype in a mixed background than they do in B6 or C3H/HeJ congenic lines [101]. The same mice on a B6 genetic background have a higher incidence of hydrocephalus, most likely due to underlying defects in ciliary structure/function [21]. Mouse strain‐dependent genetic background effects can influence the incidence of hydrocephalus in PCD mouse models. For example, Del(1)1Brk mutant mice on a B6 background usually die within the first week of life due to severe hydrocephalus, whereas mutants on a 129 background develop either mild or no hydrocephalus, indicating the presence of varying genetic modifiers in the different mouse strains [30].

Although mutations in a particular ciliopathy gene may present with a consistent phenotype, it is common for genetic modifiers to alter some of the clinical features observed within syndromes [102]. Clearly, some of the differences reported between mice and humans with mutations in syntenic genes are due to species‐specific differences in expression profiles, and/or the presence of compensatory proteins developed during divergent evolution of the species [57]. The extreme complexity of ciliary structures and functions undoubtedly accounts for most of the inter‐ and intra‐species variation in phenotypic expression. Physiological differences between these species may also greatly influence the phenotypic outcome.

Different mutations in a specific gene can produce a wide spectrum of overlapping clinical phenotypes. For example, different mutations within the human NPHP11/MKS3/TMEM67 genes can give rise to mild (NPHP), intermediate (JBTS), or severe (MKS) phenotypes [103]. Mutations involving multiple genes can be involved in individuals with Bardet–Biedl syndrome [104], and different mutations at the same locus of a single gene (CEP290) can result in three distinct disease syndromes (BBS, MKS, and NPHP) [1].

Finally, it is important to know that truncating mutations often cause severe developmental defects that result in prenatal and perinatal mortality, whereas hypomorphic mutations are more likely to cause organ specific diseases that are degenerative rather than developmental [105]. Since complete loss of ciliopathy‐associated genes often results in early lethality, it may be necessary to generate mice carrying hypomorphic alleles with a range of strengths in order to model ciliopathies [1]. The genetic mechanisms that underlie ciliary functions and thus determine ciliopathy phenotypes are extremely complex, with gene locus heterogeneity, allelic effects, and modifier genes all contributing to influence both the type and severity of disease, and pleiotropic phenotypes [106]. To further complicate matters, a growing number of ciliopathies can be classified as second order ciliopathies [15]. These include ciliopathies that are caused by mutations in genes encoding proteins not present in cilia, but that do influence cilia formation or functions. For example, there are motile ciliopathies resulting from mutations affecting specific nonciliary proteins involved in the cytosolic assembly of axonemal dynein complexes before they are imported into cilia [15].