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.

Figure 1.

Age of onset of ESRD for individuals from families with the MUC1 mutation. (This figure does not include family members who have not developed ESRD. One family has no members with ESRD and, thus, is not represented here.)

Figure 2.

Representative pedigrees from families with the MUC1 mutation. Individuals with the MUC1 mutation are represented with black symbols. Historically affected individuals are denoted with dark gray symbols. Individuals with unknown status are shown with light gray symbols. Age of ESRD (years) is given below affected individuals. The proband for each family is indicated with an arrow. A–C show families with new mutations. The age (years) of death of individuals in generation I is given below the symbol. D shows a family with earlier onset of ESRD in succeeding generations.

Figure 3.

Estimated GFR (eGFR) versus age for individuals in families with the MUC1 mutation. This graph shows the highest available eGFR measurement for affected individuals and the lowest available eGFR measurement for unaffected individuals to determine overlap. Patients in whom only the age of ESRD is available are depicted with an eGFR value of 5 ml/min per 1.73 m². There is considerable overlap between groups.

Figure 4.

Decline in eGFR over time for individuals with more than 10 eGFR measurements. Decline was rapid when eGFR was <50 ml/min per 1.73 m². The family to which each individual belongs is identified (family numbers correspond to Table 1).

Figure 5.

Age of onset of ESRD for affected parents versus children. Parental age of ESRD is plotted versus the age of ESRD for the affected child. The line represents where parental age of ESRD would equal the child’s age of ESRD. Points that are above the line represent parental ESRD age being older than the child ESRD age. Points below the line represent parental ESRD age being lower than the child ESRD age.