TY - JOUR
T1 - Novel OCRL1 Mutations in Patients With the Phenotype of Dent Disease
AU - Utsch, Boris
AU - Bökenkamp, Arend
AU - Benz, Marcus R.
AU - Besbas, Nesrin
AU - Dötsch, Jörg
AU - Franke, Ingo
AU - Fründ, Stefan
AU - Gok, Faysal
AU - Hoppe, Bernd
AU - Karle, Stephanie
AU - Kuwertz-Bröking, Eberhard
AU - Laube, Guido
AU - Neb, Margarita
AU - Nuutinen, Matti
AU - Ozaltin, Fatih
AU - Rascher, Wolfgang
AU - Ring, Troels
AU - Tasic, Velibor
AU - van Wijk, Joanna A.E.
AU - Ludwig, Michael
N1 - Funding Information: Support: Supported in part by a grant from ELAN Fonds (06.02.09.1) to B.U. Potential conflicts of interest: None.
PY - 2006/12
Y1 - 2006/12
N2 - 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. Conclusion: 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.
AB - 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. Conclusion: 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.
KW - Dent disease
KW - Lowe syndrome
KW - cataract
KW - creatine kinase (CK)
KW - lactate dehydrogenase (LDH)
KW - mental retardation
KW - oculocerebrorenal syndrome of Lowe gene (OCRL1)
KW - tubulopathy
KW - voltage-gated chloride channel and chloride/proton antiporter 5 gene (CLCN5)
UR - http://www.scopus.com/inward/record.url?scp=33845439113&partnerID=8YFLogxK
U2 - https://doi.org/10.1053/j.ajkd.2006.08.018
DO - https://doi.org/10.1053/j.ajkd.2006.08.018
M3 - Article
C2 - 17162149
SN - 0272-6386
VL - 48
SP - 942.e1-942.e14
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 6
ER -