Biallelic Expression of Mucin-1 in Autosomal Dominant Tubulointerstitial Kidney Disease: Implications for Nongenetic Disease Recognition

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetically heterogeneous renal disorder leading to progressive loss of renal function. ADTKD- REN is due to rare mutations in renin, all localized in the protein leader peptide and affecting its co-translational insertion in the endoplasmic reticulum (ER). Through exome sequencing in an adult-onset ADTKD family we identified a new renin variant, p.L381P, mapping in the mature protein. To assess its pathogenicity, we combined genetic data, computational and predictive analysis and functional studies. The L381P substitution affects an evolutionary conserved residue, co-segregates with renal disease, is not found in population databases and is predicted to be deleterious by in silico tools and by structural modelling. Expression of the L381P variant leads to its ER retention and induction of the Unfolded Protein Response in cell models and to defective pronephros development in zebrafish. Our work shows that REN mutations outside of renin leader peptide can cause ADTKD and delineates an adult form of ADTKD- REN , a condition which has usually its onset in childhood. This has implications for the molecular diagnosis and the estimated prevalence of the disease and points at ER homeostasis as a common pathway affected in ADTKD- REN , and possibly more generally in ADTKD.

Section: Introductionmentioning

confidence: 99%

Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein

Schaeffer

Izzi

Vettori

et al. 2019

“…MUT Family members carried the same clinically significant variant as the proband, WT Individuals without pathogenic variants. 3,7,8,21,22 . Early studies reported only one mutation of a single cytosine insertion in the MUC1 VNTR region.…”

Section: Discussionmentioning

confidence: 99%

Autosomal dominant tubulointerstitial kidney disease genotype and phenotype correlation in a Chinese cohort

Gong

Xia

Wang

et al. 2021

Genes of UMOD, HNF1B, MUC1, REN and SEC61A1 were reported to be associated with autosomal dominant tubulointerstitial kidney disease (ADTKD). 48 probands and their family members (N = 27) were enrolled in this genetic screening study. A combination of methods was employed for comprehensive molecular analysis of both copy number variations (CNVs) and single nucleotide variants (SNVs). 35 probands were followed for years. The phenotype-genotype and genotype-outcome correlation were inferred from these datasets. In this cohort, 18 probands were diagnosed with ADTKD, according to Kidney Disease: Improving Global Outcomes (KDIGO) guideline. Moreover, 11 probands were diagnosed with ADTKD-UMOD, one with ADTKD-REN and one with ADTKD-HNF1B, based on molecularly confirmed pathogenic variants. The 11 UMOD variants were mainly located in codons 28 to 289 and half of the variants were found to change the cysteine amino acid. According to the follow-up data, suspected ADTKD individuals had a better prognosis compared to ADTKD individuals (p = 0.029). Individuals with a cysteine substitution in the UMOD gene appeared to have a better prognosis than individuals with other amino acid substitutions (p = 0.015).

“…A rabbit anti-human MUC1fs polyclonal antibody was commercially prepared by Beijing Protein Innovation. A peptide antigen corresponding to 20 residues (NH2-SPRCHLGPGHQAGPGLHRPP-OH) of MUC1fs 14,16 was chemically synthesized and used to immunize rabbits for antibody production. Next, the rabbits were immunized with peptide-conjugated bovine serum albumin (BSA) by multiple intradermal injections.…”

Section: Generation Of Muc1fs Antibodiesmentioning

confidence: 99%

SMRT sequencing revealed to be an effective method for ADTKD-MUC1 diagnosis through follow-up analysis of a Chinese family

Wang

Rui

Dong

et al. 2020

We reported a large Chinese family diagnosed with autosomal dominant tubulointerstitial kidney disease caused by MUC1 mutation (ADTKD-MUC1). Cytosine duplication within a string of 7 cytosines in the variable-number tandem repeats (VNTR) region of the MUC1 gene was detected by long-read single-molecule real-time (SMRT) sequencing. MUC1 frameshift protein (MUC1fs) was found to be expressed in renal tubules and urinary exfoliated cells by pathological examination. The family, which consisted of 5 generations including 137 individuals, was followed for 5 years. Genetic testing was performed in thirty-four individuals, 17 of whom carried MUC1 mutations. The ADTKD-MUC1-affected individuals had an elevated incidence of hyperuricaemia without gout attack. Within five years, higher baseline levels of urinary α1-microglobulin were detected in affected individuals with rapidly progressing renal failure than in affected individuals with stable renal function, and the increases manifested even before increases in serum creatinine. This study demonstrates that SMRT sequencing is an effective method for the identification of MUC1 mutations. The pathological examination of MUC1fs expression in renal tissue and urinary exfoliated cells can contribute to early screening of family members suspected to be affected. It is suggested that affected individuals with elevated urinary α1microglobulin levels should be closely monitored for renal function. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a hereditary disease characterized by progressive tubulointerstitial nephropathy that ultimately leads to end-stage renal disease (ESRD) 1-4. To date, four genes mutation which causes ADTKD have been identified: uromodulin (UMOD) 5 , mucin-1 (MUC1) 6 , renin (REN) 7 and hepatocyte nuclear factor 1β (HNF1B) 8. The disease forms caused by these mutations were named ADTKD-UMOD, ADTKD-MUC1, ADTKD-REN and ADTKD-HNF1B, respectively. Recently, a SEC. 61A1 mutation was identified as a novel cause of ADTKD 9. The manifestations of ADTKD are nonspecific, including autosomal dominant inheritance, bland urinary sediment with absent or mild proteinuria, progressive kidney failure, and, in some cases, multiple small renal cysts 1-3,10,11. Renal histology shows interstitial fibrosis and tubular atrophy, varying degree of nephrosclerosis and arteriolar thickening. Immunofluorescence or immunostaining on the renal tissue is negative. Electron microscopy usually showed irregular width and lamelation of the glomerular basement membrane and particular the tubular basement membrane 2,12-14. The diagnosis of ADTKD-MUC1 depends on genetic analysis. The MUC1 gene, located on chromosome 1q21, contains 20-125 copies of a repetitive sequence of 60 basepair in the variable-number tandem repeats (VNTR) domain 13. Most MUC1 mutations are caused by duplication of a cytosine within a seven-cytosine stretch in the VNTR region that produces a frameshift muatation, resulting in MUC1 frameshift protein (MUC1fs) 6,14-16. In addition, mutations in other areas of ...