Characterization of a recurrent in-frame UMOD indel mutation causing late-onset autosomal dominant end-stage renal failure.
OBJECTIVE
In a single-center renal clinic, we have established routine mutation testing to diagnose UMOD-associated kidney disease (UAKD), an autosomal dominant disorder typically characterized by gout, hyperuricemia, and renal failure in the third to sixth decades.


METHODS
Four probands and their multigeneration kindreds were assessed by clinical, historical, and biochemical means. Diagnostic UMOD sequencing was performed, and mutant uromodulin was characterized in vitro.


RESULTS
All available affected members of the four kindreds harbored the same complex indel change in UMOD, which was associated with almost complete absence of gout and a later onset of CKD; the youngest age at ESRD or death was 38 years (range, 38 to 68 years) compared with 3 to 70 years in other reports. Three mutation carriers (all ≤35 years) are currently asymptomatic. The indel sequence (c.278_289del TCTGCCCCGAAGinsCCGCCTCCT; p.V93_G97del/ins AASC) results in the replacement of five amino acids, including one cysteine, by four novel residues, also including a cysteine. Uromodulin staining of the only available patient biopsy suggested disorganized intracellular trafficking with cellular accumulation. Functional characterization of the mutant isoform revealed retarded intracellular trafficking associated with endoplasmic reticulum (ER) retention and reduced secretion into cell culture media, but to a lesser extent than we observed with the previously reported C150S mutation.


CONCLUSIONS
The indel mutation is associated with a relatively mild clinical UAKD phenotype, consistent with our in vitro analysis. UAKD should be routinely considered as a causative gene for ESRD of unknown cause, especially where there is an associated family history or where biopsy reveals interstitial fibrosis.
Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
Graham D
GD
Smith
Caroline
C
Robinson
Andrew P
AP
Stewart
Emily L
EL
Edwards
Hannah I
HI
Karet
Anthony G W
AG
Norden
Richard N
RN
Sandford
Fiona E
FE
Karet Frankl
D000328:Adult; D000368:Aged; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D054643:INDEL Mutation; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000473:pathology / Q000652:urine; D008297:Male; D008875:Middle Aged; D017434:Protein Structure, Tertiary; D012008:Recurrence; D058949:Uromodulin / Q000737:chemistry / Q000235:genetics*
C548612:UMOD protein, human; D058949:Uromodulin