A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases

Abstract

With the increased availability of genomic sequencing technologies, the molecular bases for kidney diseases such as nephronophthisis and mitochondrially inherited and autosomal-dominant tubulointerstitial kidney diseases (ADTKD) has become increasingly apparent. These tubulointerstitial kidney diseases (TKD) are monogenic diseases of the tubulointerstitium and result in interstitial fibrosis and tubular atrophy (IF/TA). However, monogenic inheritance alone does not adequately explain the highly variable onset of kidney failure and extra-renal manifestations. Phenotypes vary considerably between individuals harbouring the same pathogenic variant in the same putative monogenic gene, even within families sharing common environmental factors. While the extreme end of the disease spectrum may have dramatic syndromic manifestations typically diagnosed in childhood, many patients present a more subtle phenotype with little to differentiate them from many other common forms of non-proteinuric chronic kidney disease (CKD). This review summarises the expanding repertoire of genes underpinning TKD and their known phenotypic manifestations. Furthermore, we collate the growing evidence for a role of modifier genes and discuss the extent to which these data bridge the historical gap between apparently rare monogenic TKD and polygenic non-proteinuric CKD (excluding polycystic kidney disease).

Keywords: ADTKD; genetic modifiers; modifier genes; monogenic TKD; tubulointerstitial kidney disease.

Figure 4

Gene regulatory networks in tubulointerstitial kidney disease with evidence of modifier genes, tri-allelic inheritance, or gene interaction. (a) Non-motile (primary) cilia dysfunction is a recognised driver of kidney disease, including nephronophthisis, polycystic kidney disease, or cystic dysplasia (Figure 1). Cilia are membrane-bound organelles that resemble finger-like projections on the apical surface of many tissues, including renal tubular epithelia. The primary cilium is composed of a basal body consisting of triplets of microtubules (grey) from which the cilium assembles [147]. (b) Hotspots for ciliopathies include the intraflagellar transport proteins (green) responsible for protein trafficking and signalling pathways, the inversin compartment (blue) controlling cell polarity, the transition zone (purple) involved in the cell cycle and control of the entry and exit of proteins, and the BBSome (Bardet–Biedl syndrome proteins) (red) responsible for the trafficking of proteins to the cilia [147]. This network of selected genes with evidence of modifier and tri-allelic inheritance reveals the close functional interaction of genes encoding the primary cilia. Solid lines represent modifier genes, and dashed lines represent genes with evidence for possible tri-allelic inheritance. The direction of the arrow denotes the direction of the contribution of additional variants to the primary mutated gene (e.g., homozygous variants in NPHP1 and a third mutated allele in AHI1 may result in a neurological phenotype like Joubert syndrome) [41]. Bidirectional arrows indicate the equal contribution of variants. (c) There is significant potential for cumulative variantal burden in genes downstream of the transcription factor hepatocyte nuclear factor 1β (HNF1B) to modify disease phenotypes. Evidence in mouse models suggests that several genes are downregulated with Hnf1b inactivation (dashed line) [92]. Downregulation of UMOD may also explain why most patients with HNF1B variants have hyperuricaemia typical of ADTKD-UMOD [148]. Loss of HNF1B results in activation of a transcriptional network that induces extracellular matrix deposition and aberrant transforming growth factor 1 beta (TGF1B) signalling, resulting in tubulointerstitial fibrosis [149]. HNF1B is linked to mitochondrial dysfunction in renal epithelial cells in experimental studies through other transcription factors [150]. Mitochondrial dysfunction in ADTKD-UMOD also results secondary to endoplasmic reticulum stress from retention of misfolded uromodulin protein [133]. Direct evidence of genetic modification has been reported in a patient with heterozygous variants in both PKD1 and HNF1B, causing early-onset severe disease [130].

Figure 1

Synonymous and umbrella terms in tubulointerstitial kidney disease (TKD).

Figure 2

Simplified schematic representation of complex genetic inheritance from monogenic to polygenic (boxes represent genes; red vertical lines represent the pathogenic allele). A spectrum of increasingly complex diseases may occur with additional mutated alleles from monoallelic through to multiallelic. Additional complexity arises due to the number of genes affected from one gene (monogenic), a few genes (oligogenic), or many genes (polygenic). Modifiers are variants that can alter the disease phenotype but are not required for the primary disease to be present. Modifiers can be additive or suppressive and can affect penetrance, expressivity, and dominance.

Figure 3

The spectrum of disease associated with variants in centrosomal protein 290 (CEP290). (a) Eye involvement ranges from a relatively mild retinal phenotype to Leber congenital amaurosis (LCA), which is a leading cause of childhood blindness. (b) Senior–Løken syndrome is characterised by retinal dystrophy and nephronophthisis. (c) Joubert syndrome (JBTS) adds cerebellar vermis hypoplasia to retinal dystrophy and nephronophthisis. (d) Bardet–Biedl syndrome is truly multisystem, with significant features of retinal disease, central obesity, postaxial polydactyly, cognitive impairment, genitourinary abnormalities, and kidney disease. (e) Meckel–Gruber syndrome is a lethal multisystem disorder with occipital meningo-encephalocele, hepatobiliary ductal plate malformation, postaxial polydactyly, and cystic dysplasia of the kidneys with marked interstitial fibrosis.