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Human Molecular Genetics Advance Access originally published online on January 28, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 6 617-627
DOI: 10.1093/hmg/ddh067

Molecular pathophysiology of mucolipidosis type IV: pH dysregulation of the mucolipin-1 cation channel

Malay K. Raychowdhury1,2,{dagger}, Silvia González-Perrett3,4,{dagger}, Nicolás Montalbetti3, Gustavo A. Timpanaro3, Bernard Chasan5, Wolfgang H. Goldmann1,2, Stefanie Stahl6, Adele Cooney6, Ehud Goldin6 and Horacio F. Cantiello1,2,3,*

1Renal Unit, Massachusetts General Hospital East, Charlestown, MA, USA, 2Department of Medicine, Harvard Medical School, Boston, MA, USA, 3Laboratorio de Canales Iónicos, Departamento de Fisicoquímica y Química Analítica, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina, 4Departamento de Fisiología, Facultad de Medicina, Buenos Aires, Argentina, 5Physics Department, Boston University, Boston, MA, USA and 6Developmental and Metabolic Neurology Branch, National Institutes of Health, Bethesda, MD, USA

Received October 28, 2003; Revised January 12, 2004; Accepted January 25, 2004

Mucolipidosis type IV (MLIV) is an autosomal recessive neurogenetic disorder characterized by developmental abnormalities of the brain and impaired neurological, ophthalmologic and gastric function. Large vacuoles accumulate in various types of cells in MLIV patients. However, the pathophysiology of the disease at the cellular level is still unknown. MLIV is caused by mutations in a recently described gene, MCOLN1, encoding mucolipin-1 (ML1), a 65 kDa protein whose function is also unknown. ML1 shows sequence homology and topological similarities with polycystin-2 and other transient receptor potential (Trp) channels. In this study, we assessed both, whether ML1 has ion channel properties, and whether disease-causing mutations in MCOLN1 have functional differences with the wild-type (WT) protein. ML1 channel function was assessed from endosomal vesicles of null (MCOLN1–/–) and ML1 over-expressing cells, and liposomes containing the in vitro translated protein. Evidence from both preparations indicated that WT ML1 is a multiple subconductance non-selective cation channel whose function is inhibited by a reduction of pH. The V446L and {Delta}F408 MLIV causing mutations retain channel function but not the sharp inhibition by lowering pH. Atomic force imaging of ML1 channels indicated that changes in pH modified the aggregation of unitary channels. Mutant-ML1 did not change in size on reduction of pH. The data indicate that ML1 channel activity is regulated by a pH-dependent mechanism that is deficient in some MLIV causing mutations of the gene. The evidence also supports a novel role for cation channels in the acidification and normal endosomal function.

* To whom correspondence should be addressed at: Renal Unit, Massachusetts General Hospital East, 149 13th Street, Charlestown, MA 02129, USA. Tel: +1 6177265640; Fax: +1 6177265669; Email: cantiello{at}helix.mgh.harvard.edu


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