DIFFERENT DISEASE COURSES IN ADTKD
What impact do gene networks have?
09/03/2024 - Inherited genetic variants that cause a defect in certain genes are the cause of autosomal dominant tubulointerstitial kidney disease (ADTKD). ADTKD is classified as a monogenic disease because the disease is usually caused by a single variant in a family. However, there can be significant differences within a family as to when the disease breaks out and how quickly it leads to kidney failure. Scientists have been looking for explanations for these different disease courses for some time. One possible cause of this is so-called modifying genes.
The latest findings on such modifying genes in tubulointerstitial kidney diseases (TKD), including ADTKD, are summarized in a British review. The authors consider the idea that a single gene determines a disease phenotype (appearance) to be outdated. They therefore criticize the strict separation of monogenic diseases (the disease-causing mutation is on one gene and has a strong effect) and polygenic diseases (many common variants in different genes, each with a small effect, lead to the disease). Rather, there is clear evidence that TKD can be influenced by a variety of modifiers. This can happen both through environmental influences and through additional genes.
WHAT ARE MODIFYING GENES?
Modifying genes are not necessary to cause the disease, but they affect the phenotype in different ways. The expression and function of another gene can be influenced at several levels, including transcription (the reading of DNA information and its conversion into a new messenger RNA) and the interaction of proteins at the molecular and cellular level. As a result, genetic modifiers can affect the penetrance (the likelihood that a change will lead to a phenotype) and the severity of a disease, and can have both enhancing and suppressing effects.
A phenotype can be altered not only by modifiers in other genes, but also by other variants that occur in the same gene as the causative mutation. According to current knowledge, this also applies to the ADTKD subtypes UMOD and MUC1.
GENETIC MODIFYERS IN ADTKD-UMOD
It is suspected that a variant (rs4293393) in the causative UMOD gene that is relatively common in the general population reduces the expression of the protein uromodulin in the subtype ADTKD-UMOD. A study of 147 ADTKD-UMOD families found that this variant is less common than expected on the allele with the disease-causing mutation. Since it downregulates the production of the mutated and thus disease-causing uromodulin and thus presumably causes a milder phenotype, this variant in combination with a mutation probably has a protective effect.
GENETIC MODIFYERS IN ADTKD-MUC1
ADTKD-MUC1 is most commonly caused by the insertion of an additional base into a specific gene section (VNTR). This causes a shift (frameshift) in the genetic information so that it is no longer read correctly. This form is very difficult to study using current sequencing methods due to the repetitive base sequence in the VNTR region, which is why ADTKD-MUC1 is probably underdiagnosed.
A variant (rs4072037) in MUC1, which is widespread in the population, encodes signal peptides of different lengths and results in different mucin-1 serum levels depending on the genotype. Mucin-1 (CA15-3) levels in plasma of ADTKD MUC1 patients and controls were recently investigated. It was found that the rs4072037 genotype alone did not improve the discrimination between affected and unaffected individuals. The authors suggested that this could be explained by the fact that the VNTR is of different length and there is no information on which gene copy the variant is located on. New sequencing methods that can determine the length and phase (location of the common variant in relation to the familial mutation) are being used by the recently funded European consortium “ADTKD-Net” to further investigate this variant and its impact on the phenotype.
ADTKD-HFN1B
Patients with ADTKD-HNF1B also exhibit a remarkable variety of clinical pictures, ranging from rapid renal failure to a nearly asymptomatic course. The different disease courses may be due to how HNF1β affects the transcription of many other genes. In addition, different HNF1B mutations are associated with different kidney diseases, including copy number alterations (loss/gain of genetic material) or small variations that result in protein loss or replacement of individual protein building blocks. There are 14 neighboring genes in the affected chromosomal region 17q12, which may account for some variability between CNV carriers. Most HNF1B patients exhibit haploinsufficiency, resulting in a reduction in HNF1β protein activity of approximately 50%. However, depending on the modified factors, this may be higher and even close to a potentially disease-critical threshold. These modifiers are searched for by the “ADTKD-Net” consortium.
IMPLICATIONS FOR TREATMENT AND FUTURE RESEARCH DIRECTIONS
Diagnosis and treatment of TKD could be improved by better understanding how such modifiers work. In the future, tailored treatment plans could be developed based on a person's individual genetic makeup, including the primary variant and modifier genes.
To gain a better understanding of their function in TKD, the authors call for further investigation of genetic modifiers. The widespread application of new genomic technologies could provide deeper insights into the development and progression of these diseases.
Expert advice: Dr. Bernt Popp, Berlin Institute of Health at Charité
Sources:
Legatt GP et al. A Role for Genetic Modifiers in Tubulointerstitial Kidney. Genes (Basel). 2023 Aug 3;14(8):1582
Vylet’al et al. Plasma Mucin-1 (CA15-3) Levels in Autosomal Dominant Tubulointerstitial Kidney Disease due to MUC1 Mutations. Am J Nephrol. 2021; 52(5):378–387