Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.

• Keywords
• ADTKD, HNF-1B, MUC-1, UMOD, chronic kidney disease, frameshift, genetic, urinary smear,
• MeSH
• Kidney Failure, Chronic epidemiology   genetics   pathology   MeSH
• Genes, Dominant * MeSH
• Adult MeSH
• Genetic Testing statistics & numerical data   MeSH
• Hepatocyte Nuclear Factor 1-beta genetics   MeSH
• Kidney Tubules pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mucin-1 genetics   MeSH
• Mutation MeSH
• Prevalence MeSH
• Cross-Sectional Studies MeSH
• Aged MeSH
• Uromodulin genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Geographicals
• Ireland epidemiology   MeSH
• Names of Substances
• Hepatocyte Nuclear Factor 1-beta MeSH
• HNF1B protein, human MeSH Browser
• MUC1 protein, human MeSH Browser
• Mucin-1 MeSH
• UMOD protein, human MeSH Browser
• Uromodulin MeSH

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (MUC1) mutations (ADTKD-MUC1) is characterized by progressive kidney failure. Genetic evaluation for ADTKD-MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein. METHODS: We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-MUC1-positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations. RESULTS: After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein. CONCLUSIONS: We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-MUC1.

• Keywords
• Autosomal Dominant Tubulo-Interstitial Kidney Disease, Inherited, MUC1, Mucin-1 Kidney Disease, diagnosis, immunostaining, kidney disease,
• MeSH
• Genetic Predisposition to Disease epidemiology   MeSH
• Risk Assessment MeSH
• Immunohistochemistry MeSH
• Incidence MeSH
• Biopsy, Needle MeSH
• Humans MeSH
• Mucin-1 genetics   MeSH
• Mutation genetics   MeSH
• Polycystic Kidney, Autosomal Dominant genetics   mortality   pathology   MeSH
• Prognosis MeSH
• Registries MeSH
• Retrospective Studies MeSH
• Pedigree MeSH
• Case-Control Studies MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• MUC1 protein, human MeSH Browser
• Mucin-1 MeSH

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is characterized by autosomal dominant inheritance, progressive chronic kidney disease, and a bland urinary sediment. ADTKD is most commonly caused by mutations in the UMOD gene encoding uromodulin (ADTKD-UMOD). We herein report the first confirmed case of a multi-generational Brazilian family with ADTKD-UMOD, caused by a novel heterozygous mutation (c.163G>A, GGC→AGC, p.Gly55Ser) in the UMOD gene. Of 41 family members, 22 underwent genetic analysis, with 11 individuals found to have this mutation. Three affected individuals underwent hemodialysis, one peritoneal dialysis, and one patient received a kidney transplant from a family member later found to be genetically affected. Several younger individuals affected with the mutation were also identified. Clinical characteristics included a bland urinary sediment in all tested individuals and a kidney biopsy in one individual showing tubulointerstitial fibrosis. Unlike most other reported families with ADTKD-UMOD, neither gout nor hyperuricemia was found in affected individuals. In summary, we report a novel UMOD mutation in a Brazilian family with 11 affected members, and we discuss the importance of performing genetic testing in families with inherited kidney disease of unknown cause.

• MeSH
• Biopsy MeSH
• Genotype MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation genetics   MeSH
• Polycystic Kidney, Autosomal Dominant genetics   pathology   MeSH
• Pedigree MeSH
• Uromodulin genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• UMOD protein, human MeSH Browser
• Uromodulin MeSH

Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.

• MeSH
• Alleles MeSH
• Anemia genetics   MeSH
• Biopsy MeSH
• Chronic Disease MeSH
• Zebrafish embryology   genetics   MeSH
• Child MeSH
• Genes, Dominant MeSH
• Adult MeSH
• Endoplasmic Reticulum metabolism   MeSH
• Exome genetics   MeSH
• Phenotype MeSH
• Golgi Apparatus metabolism   MeSH
• Heterozygote * MeSH
• Middle Aged MeSH
• Humans MeSH
• RNA, Messenger analysis   genetics   MeSH
• Mutation, Missense genetics   MeSH
• Young Adult MeSH
• Models, Molecular MeSH
• Mutation * MeSH
• Kidney Diseases genetics   pathology   MeSH
• Neutropenia genetics   MeSH
• Infant, Newborn MeSH
• Disease Progression MeSH
• Pedigree MeSH
• Fetal Growth Retardation genetics   MeSH
• Amino Acid Sequence MeSH
• Aged MeSH
• Syndrome MeSH
• SEC Translocation Channels chemistry   genetics   MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Infant, Newborn MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• RNA, Messenger MeSH
• SEC61A1 protein, human MeSH Browser
• SEC Translocation Channels MeSH

Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.

• MeSH
• Gout * classification   diagnosis   genetics   therapy   MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Hyperuricemia * classification   diagnosis   genetics   therapy   MeSH
• Consensus MeSH
• Humans MeSH
• Mutation MeSH
• DNA Mutational Analysis MeSH
• Nephrology standards   MeSH
• Kidney Diseases * classification   diagnosis   genetics   therapy   MeSH
• Polycystic Kidney, Autosomal Dominant * classification   diagnosis   genetics   therapy   MeSH
• Predictive Value of Tests MeSH
• Terminology as Topic MeSH
• Uromodulin classification   deficiency   genetics   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Consensus Development Conference MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Practice Guideline MeSH
• Names of Substances
• Uromodulin MeSH