Variable Clinical Presentation of an MUC1 Mutation Causing Medullary Cystic Kidney Disease Type 1

Abstract

Background and objectives The genetic cause of medullary cystic kidney disease type 1 was recently identified as a cytosine insertion in the variable number of tandem repeat region of MUC1 encoding mucoprotein-1 (MUC1), a protein that is present in skin, breast, and lung tissue, the gastrointestinal tract, and the distal tubules of the kidney. The purpose of this investigation was to analyze the clinical characteristics of families and individuals with this mutation.Design, setting, participants, & measurements Families with autosomal dominant interstitial kidney disease were referred for genetic analysis over a 14-year period. Families without UMOD or REN mutations prospectively underwent genotyping for the presence of the MUC1 mutation. Clinical characteristics were retrospectively evaluated in individuals with the MUC1 mutation and historically affected individuals (persons who were both related to genetically affected individuals in such a way that ensured that they could be genetically affected and had a history of CKD stage IV or kidney failure resulting in death, dialysis, or transplantation).Results Twenty-four families were identified with the MUC1 mutation. Of 186 family members undergoing MUC1 mutational analysis, the mutation was identified in 95 individuals, 91 individuals did not have the mutation, and111 individuals were identified as historically affected. Individuals with the MUC1 mutation suffered from chronic kidney failure with a widely variable age of onset of end stage kidney disease ranging from 16 to .80 years. Urinalyses revealed minimal protein and no blood. Ultrasounds of 35 individuals showed no medullary cysts. There were no clinical manifestations of the MUC1 mutation detected in the breasts, skin, respiratory system, or gastrointestinal tract.Conclusion MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. The age of onset of end stage kidney disease is highly variable, suggesting that gene-gene or gene-environment interactions contribute to phenotypic variability.

The Irish Kidney Gene Project - Prevalence of Family History in Patients with Kidney Disease in Ireland

“…Increasingly genes are being identified for conditions which were not previously associated with familial inheritance. Identification of the MUC1 mutation in families with medullary cystic kidney disease has helped redefine and characterize tubulo-interstitial kidney disease in cases where there were no associated features except progressive kidney disease [8,19]. In an Irish population, a hybrid CFHR3-1 gene has been found to be associated with familial C3 glomerulopathy [20].…”

“…Single gene defects in NPHS1 (podocin) and NPHS2 (nephrin) lead to steroid-resistant nephrotic syndrome in children [7]. More recently, the identification of the MUC1 mutation in families with medullary cystic kidney disease has allowed for characterization and reclassification of interstitial renal diseases [8.] Analysis of these genes has allowed for establishment of definitive diagnosis, prognostication in terms of age of onset of disease and risk of progression to ESKD.…”

Bases moleculares e celulares das nefropatias hereditárias císticas

“…Gota e hipertensão arterial, não são manifestações primárias na DRIAD1, embora possam ocorrer secundariamente à perda de função renal em estágio avançado de doença renal crônica 47,48 . O gene associado à DRIAD1 foi identificado apenas em 2013.…”

“…Uma possibilidade é que Muc1 aberrante não sofra processamento pós-translacional, perdendo suas propriedades originais de ancoramento transmembrânico e seus domínios de sinalização intracelular. A neoproteina formada pode se acumular no interior das células tubulares renais e induzir morte celular 48 .…”

Variable Presentations of Rare Genetic Renal Interstitial Diseases

“…The report by Anthony Bleyer and his colleagues in this issue of CJASN vividly illustrates the problem encountered by nephrologists who must make the diagnosis of supposedly rare conditions (2). Over a 14-year period, this international team has assembled a sample of approximately 400 families with hereditary interstitial kidney disease.…”