Novel OCRL1 mutations in patients with the phenotype of Dent disease.
BACKGROUND
Dent disease is an X-linked tubulopathy frequently caused by mutations affecting the voltage-gated chloride channel and chloride/proton antiporter ClC-5. A recent study showed that defects in OCRL1, encoding a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ocrl) and usually found mutated in patients with Lowe syndrome, also can provoke a Dent-like phenotype (Dent 2 disease).


METHODS
We investigated 20 CLCN5-negative males from 17 families with a phenotype resembling Dent disease for defects in OCRL1.


RESULTS
In our complete series of 35 families with a phenotype of Dent disease, a mutation in the OCRL1 gene was detected in 6 kindreds. All were novel frameshift (Q70RfsX88 and T121NfsX122, detected twice) or missense mutations (I257T and R476W). None of our patients had cognitive or behavioral impairment or cataracts, 2 classic hallmarks of Lowe syndrome. All patients had mild increases in lactate dehydrogenase and/or creatine kinase levels, which rarely is observed in CLCN5-positive patients, but frequently found in patients with Lowe syndrome. To explain the phenotypic heterogeneity caused by OCRL1 mutations, we performed extensive data-bank mining and extended reverse-transcriptase polymerase chain reaction analysis, which provided no evidence for yet unknown (tissue-specific) alternative OCRL1 transcripts.


CONCLUSIONS
Mutations in the OCRL1 gene are found in approximately 23% of kindreds with a Dent phenotype. Defective protein sorting/targeting of Ocrl might be the reason for mildly elevated creatine kinase and lactate dehydrogenase serum concentrations in these patients and a clue to suspect Dent disease unrelated to CLCN5 mutations. It remains to be elucidated why the various OCRL1 mutations found in patients with Dent 2 disease do not cause cataracts.
Utsch
Boris
B
Klinik mit Poliklinik für Kinder und Jugendliche, Universität Erlangen-Nürnberg, Erlangen, Germany.
Bökenkamp
Arend
A
Benz
Marcus R
MR
Besbas
Nesrin
N
Dötsch
Jörg
J
Franke
Ingo
I
Fründ
Stefan
S
Gok
Faysal
F
Hoppe
Bernd
B
Karle
Stephanie
S
Kuwertz-Bröking
Eberhard
E
Laube
Guido
G
Neb
Margarita
M
Nuutinen
Matti
M
Ozaltin
Fatih
F
Rascher
Wolfgang
W
Ring
Troels
T
Tasic
Velibor
V
van Wijk
Joanna A E
JA
Ludwig
Michael
M
D018118:Chloride Channels / Q000235:genetics; D003402:Creatine Kinase / Q000097:blood; D016368:Frameshift Mutation; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D020125:Mutation, Missense; D009800:Oculocerebrorenal Syndrome / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D021381:Protein Transport / Q000502:physiology; D015499:Renal Tubular Transport, Inborn Errors / Q000097:blood / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
C097539:CLCN6 protein, human; D018118:Chloride Channels; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human