title: Renal fibrosis is the common feature of autosomal dominant tubulointerstitial kidney diseases caused by mutations in mucin 1 or uromodulin.
abstract: For decades, ill-defined autosomal dominant renal diseases have been reported, which originate from tubular cells and lead to tubular atrophy and interstitial fibrosis. These diseases are clinically indistinguishable, but caused by mutations in at least four different genes: UMOD, HNF1B, REN, and, as recently described, MUC1. Affected family members show renal fibrosis in the biopsy and gradually declining renal function, with renal failure usually occurring between the third and sixth decade of life. Here we describe 10 families and define eligibility criteria to consider this type of inherited disease, as well as propose a practicable approach for diagnosis. In contrast to what the frequently used term 'Medullary Cystic Kidney Disease' implies, development of (medullary) cysts is neither an early nor a typical feature, as determined by MRI. In addition to Sanger and gene panel sequencing of the four genes, we established SNaPshot minisequencing for the predescribed cytosine duplication within a distinct repeat region of MUC1 causing a frameshift. A mutation was found in 7 of 9 families (3 in UMOD and 4 in MUC1), with one indeterminate (UMOD p.T62P). On the basis of clinical and pathological characteristics we propose the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' as an improved terminology. This should enhance recognition and correct diagnosis of affected individuals, facilitate genetic counseling, and stimulate research into the underlying pathophysiology.
authors.affiliation: Institute for Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: 1] Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany [2] Nikolaus-Fiebiger-Center of Molecular Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hackenbeck
authors.affiliation: Department of Genetics, Assistance Publique-Hopitaux de Paris, Necker Hospital, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Morinière
authors.affiliation: Institute for Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pannes
authors.affiliation: Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Buettner
authors.affiliation: Institute for Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Department of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Janka
authors.affiliation: Institute for Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Wiesener
authors.affiliation: 1] Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany [2] Nikolaus-Fiebiger-Center of Molecular Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Hermann
authors.affiliation: 1] Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany [2] Nikolaus-Fiebiger-Center of Molecular Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Grupp
authors.affiliation: Department of Nephrology and Hypertension, Hospital of Offenburg, Offenburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hornberger
authors.affiliation: 1] Renal Division, University Hospital Freiburg, Freiburg, Germany [2] BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.affiliation: Department of Renal Medicine, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Nikky
authors.initials: N
authors.lastname: Isbel
authors.affiliation: Department of Renal Medicine, St George Clinical School, University of New South Wales, Kogarah, New South Wales, Australia.
authors.forename: George
authors.initials: G
authors.lastname: Mangos
authors.affiliation: Department of Renal Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia.
authors.forename: Stella
authors.initials: S
authors.lastname: McGinn
authors.affiliation: KfH Nierenzentrum Miesbach, Miesbach, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Soreth-Rieke
authors.affiliation: Institute for Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Bodo B
authors.initials: BB
authors.lastname: Beck
authors.affiliation: Department of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Uder
authors.affiliation: Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.affiliation: 1] Inserm, U983, Necker Hospital, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.affiliation: Institute for Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.affiliation: 1] Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany [2] Nikolaus-Fiebiger-Center of Molecular Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wiesener
mesh_terms: D001284:Atrophy; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1; D002885:Chromosomes, Human, Pair 16; D005260:Female; D005355:Fibrosis; D006239:Haplotypes; D006801:Humans; D007684:Kidney Tubules / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D018396:Mucin-1 / Q000235:genetics*; D009395:Nephritis, Interstitial / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D009626:Terminology as Topic; D058949:Uromodulin / Q000235:genetics*
chemical_list: D018396:Mucin-1; D058949:Uromodulin