Human Molecular Genetics, 2000, Vol. 9, No. 17 2471-2478
© 2000 Oxford University Press
Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel
1Developmental and Metabolic Neurology Branch, 2DNA Sequencing Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA, 3Harvard Institute of Human Genetics, Harvard Medical School, Boston, MA 02115, USA and 4Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA
Received 17 August 2000; Revised and Accepted 27 August 2000.
DDBJ/EMBL/GenBank accession nos AF287269, AF287270.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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Mucolipidosis type IV (MLIV) is a developmental neurodegenerative disorder characterized by severe neurologic and ophthalmologic abnormalities. The MLIV gene, ML4 (MCOLN1), has recently been localized to chromosome 19p13.2–13.3 by genetic linkage. Here we report the cloning of a novel transient receptor potential cation channel gene and show that this gene is mutated in patients with the disorder. ML4 encodes a protein, which we propose to call mucolipin, which has six predicted transmembrane domains and is a member of the polycystin II subfamily of the Drosophila transient receptor potential gene family. The role of a potential receptor-stimulated cation channel defect in the pathogenesis of mucolipidosis IV is discussed.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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Mucolipidosis type IV (MLIV; MIM 252650) is an autosomal recessive developmental disorder with abnormal brain, eye and gastric functions. It was first described by Berman et al. (1) who studied an Ashkenazi Jewish infant with corneal clouding, a variety of storage bodies and large vacuoles in many different cell types, in the presence of normal levels of lysosomal hydrolases. The lack of identification of a specific storage compound led to the mucolipidosis classification. Other diseases in this class are mucolipidosis I (sialidosis), which is caused by sialidase (lysosomal neuraminidase) deficiency, mucolipidosis II (I-cell disease) and III (pseudo-Hurler polydystrophy), which are caused by the deficiency of N-acetylglucosamine-1-phosphotransferase (2).
Clinically, MLIV is characterized by a variable degree of growth and psychomotor retardation that is apparent as early as the first year of life. Most patients are unable to speak or walk independently and remain developmentally at a 1–2 year level. Patient head MRI at the time of diagnosis shows a dysplastic corpus callosum and dysmyelinating white matter abnormalities indicating early onset of brain pathology, whereas cerebellar atrophy is seen predominantly in older patients (3). MLIV is further characterized by corneal clouding and a progressive retinopathy with optic atrophy, which results in severe visual impairment (4). The majority of MLIV patients appear to have a static encephalopathy and do not deteriorate neurologically; however, some patients show a decline in motor function in the second or third decade of life. A simple approach to the diagnosis of MLIV was obtained when we discovered that all patients have constitutive achlorhydria associated with a secondary elevation of serum gastrin levels (5). At the present time, MLIV is the only genetic disease known to be associated with elevated gastrin.
We have mapped the gene that is mutated in MLIV, ML4 (MCOLN1), to a 5.6 cM region on chromosome 19p13.2–13.3 by linkage analysis in 26 Ashkenazi Jewish (AJ) families (6). In addition, we have determined that the ethnic bias seen in MLIV is due to a founder effect, with two common haplotypes representing 96% of the chromosomes. Utilizing our finding that the storage bodies in MLIV fibroblasts are autofluorescent (7), we were able to implicate a single gene defect in both AJ and non-Jewish (NJ) patients (8) by complementation assays. Recently, we have collected an additional nine AJ and five NJ families and conducted a detailed haplotype analysis in order to pinpoint the gene location and determine the probable number of mutations. There are five unique haplotypes in the AJ population, the major and minor haplotypes are present on 73 and 23% of chromosomes, respectively. The remaining three haplotypes were only seen once: in two cases coupled with the major and one with the minor haplotype. Analysis of the five NJ families yielded an additional eight unique haplotypes, suggesting that there may be as many as 13 independent mutations. Linkage disequilibrium analysis of the two common haplotypes enabled us to narrow the candidate region to 143 kb and we constructed a detailed transcript map of this interval (J.S. Acierno, J.C. Kennedy, J. Falardeau, M.C. Bromley, M. Colman, M. Leyne, M. Sun, C. Bove, L.K. Ashworth, T. Schiripo et al., manuscript in preparation). Analysis of the candidate genes revealed that mutations in a novel member of the polycystin II family of the transient receptor potential (TRP) channel gene family result in MLIV.
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RESULTS |
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Determination of the candidate interval
Following our initial report of linkage, we obtained a physical map consisting of overlapping bacterial artificial chromosomes (BACs) and cosmids from collaborators at Lawrence Livermore National Laboratory (LLNL). By localizing the linked markers on this map, we were able to narrow the candidate interval to
550 kb. Our recent haplotype analysis utilizing eight new genetic markers allowed further reduction of the candidate region to 143 kb between the markers D19S1184 and D19S1186, a distance covered by two BACs (BC672420, GenBank accession no. AC008878 and BC903416, GenBank accession no. AC008763) and one cosmid (R31913, GenBank accession no. AC009003) (Fig. 1) (J.S. Acierno et al., manuscript in preparation).
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Isolation of candidate genes
A combination of exon trapping and expressed sequence tag (EST) mapping was used to identify ML4 candidate genes. Once identified, we assembled the known ESTs and used direct sequence prediction of the genomic DNA in order to obtain the full-length cDNA sequences. In some cases, individual cDNA clones were purchased and sequenced to verify the predicted sequence. Examination of Genemap’99 showed 27 unique ESTs that potentially mapped to the 550 kb ML4 candidate region. PCR of the BACs and cosmids demonstrated that six of these were located between the markers D19S1184 and D19S1186. Three of the six represented the previously identified genes KIAA0521, neuropathy target esterase (NTE) and a small single exon zinc finger gene (GenBank accession no. AK001252), which we called MG-1. The remaining three ESTs represented novel genes and were named MG-2, MG-4 and MG-12. Exon trapping experiments yielded 11 unique exons from KIAA0521, NTE, MG-4 and MG-2. The exons that were trapped from MG-2 were found to match Unigene cluster Hs.12909 and we sequenced the IMAGE clone 2517653. We then designed PCR primers that flanked the putative start and stop codon and amplified a 2025 bp cDNA from control fibroblasts. Comparison of this sequence with the EST sequences enabled us to confirm that MG-2 contains a 1740 bp open reading frame (ORF) that encodes a 580 amino acid protein (GenBank accession no. AF287269). The genomic structure of MG-2 was determined by aligning the cDNA sequence against the genomic sequence of BC672420. MG-2 is composed of 14 exons that span 13 270 bp of genomic DNA. A schematic representation of the gene is presented in Figure 1. Systematic hybridization of northern blots containing patient and control RNA with probes made from ML4 candidate genes showed a deficiency of the message for MG-2 in AJ MLIV patients homozygous for the major haplotype, heterozygous for the major and minor haplotypes and homozygous for the minor haplotype (Fig. 2A, lanes 2, 4 and 6, respectively), implicating this gene in the pathogenesis of the disease. This finding suggested that MG-2 was probably ML4 and prompted us to search for mutations in the gene.
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Identification of mutations in ML4
In order to identify the mutations resulting in the decreased expression of ML4 in AJ patients, PCR was performed using cDNA made from patients that were homozygous for either the major or minor Jewish haplotype. PCR using primers designed to amplify the entire 2025 bp cDNA produced a single product of the expected size in control cDNA, several shorter bands in the major haplotype cDNA and no band in the minor haplotype cDNA (data not shown). Sequence analysis of several clones obtained from RT–PCR of the major haplotype revealed the deletion of exon 4 and various partial deletions of exon 5. Analysis of genomic DNA using primers that flank exons 3 and 4 showed an A
G substitution at the 3' acceptor site of intron 3 (Table 1). This mutation is the likely cause of the apparent deletion of exon 4 in the mRNA. This substitution creates a KpnI restriction site that permits simple detection of the mutation by digestion following PCR using the primers mg2-EF4 and mg2-ER4 (Fig. 1). Following digestion with KpnI, carriers of the major mutation show the predicted 541, 344 and 197 bp fragments (lane 1), patients homozygous for the mutation show only the smaller fragments (lane 2) and controls show only the 541 bp fragment (lane 3) (Fig. 2B).
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Southern blots performed using DNA from a patient homozygous for the minor AJ haplotype showed the absence of a 3.4 kb BamHI fragment that spanned exons 2–5 (data not shown). PCR using several sets of primers outside this area showed that the DNA 1 kb upstream of ML4 and downstream from exon 7 was intact. In order to identify the boundaries of the genomic deletion, we performed genomic walking with primers downstream of exon 7 and demonstrated that the mutation on the minor Jewish haplotype is a 6434 bp deletion (Table 1). The deletion extends from 511 to 6945 bp of the ML4 genomic sequence (GenBank accession no. AF287270) and spans exons 1–6 and the first 12 bp of exon 7. The extent of the deletion was confirmed by sequencing PCR products generated from the minor haplotype using the primers mg2-GWF4 and mg2-ER6, which flank the deletion (Figs 1 and 2C). Patients who are homozygous for the minor AJ haplotype are missing the 541 bp fragment used for identification of the major haplotype and appear blank in Figure 2B (lane 6). It follows, therefore, that patients who are heterozygous for the major and minor AJ haplotypes appear homozygous for the major haplotype (Fig. 2B, lane 4).
We also studied two AJ patients who are heterozygous for the major mutation and a unique haplotype (families 20 and 44) and one AJ patient who is heterozygous for the minor mutation and a unique haplotype (family 18). Given the results of our previous complementation studies implicating a single gene in both AJ and NJ patients, we also examined five NJ families 41, 42, 48, 50 and 53 for expression of ML4. Two of these families, 41 and 48, are consanguineous and are homozygous for all of the markers in the 19p13.2–13.3 region. Families 42 and 50 are heterozygous for unique haplotypes and family 53 is heterozygous for a unique haplotype and the family 48 haplotype. Expression levels were evaluated in patient fibroblasts (Fig. 2A) in all cases except family 44, for whom only lymphoblasts were available (Fig. 2D). Expression of ML4 was absent in the AJ patient from family 18 but normal in the patients from families 20 and 44 (Fig. 2A and D). Interestingly, the patient in family 20 has previously been reported to have an extremely mild phenotype (9). In the NJ patients, high expression of ML4 is evident in families 41, 42, 48 and 53, whereas there is no expression in the patient in family 50 (Fig. 2D). All five NJ patients were screened for the major and minor Jewish mutations and interestingly the patient in family 50 was found to be heterozygous for the 6434 bp deletion (Table 1). On testing the parents, the mother was found to carry the AJ deletion mutation. The haplotype in family 50 for the four markers closest to ML4 is completely different from the minor AJ haplotype and at this time we cannot exclude the possibility that this deletion occurred twice on different genetic that backgrounds. However, we feel that it is more likely that the mother has AJ ancestry and that this haplotype is, in fact, distantly related to the minor AJ haplotype.
In order to identify ML4 mutations in these patients, we designed overlapping sets of primers and amplified segments of the gene from patient lymphoblast or fibroblast cDNA. We also designed primers that would permit the amplification of each exon from genomic DNA. Mutations were identified for the unique haplotypes in families 18, 20, 41, 42, 48, 50 and 53 (Table 1). Two of the mutations cause frameshifts that predict truncated proteins, 18 and 50. Mutations in 41 and 42 result in amino acid substitutions, both of which occur inside the putative transmembrane domains and the unique mutation in family 20 results in the deletion of an amino acid that is located on the edge of the fourth predicted transmembrane domain. The base pair substitution in family 48 creates a new preferred splice acceptor site at base pair 47 of exon 12 and results in a frameshift. The mutations in families 42 and 53 carry base substitutions that create stop codons in exons 3 and 4, respectively.
Characterization of ML4
Northern analysis of various human tissues shows that the ML4 message is ubiquitously expressed in adult and fetal tissues (data not shown). The predicted full-length protein, mucolipin, is 580 amino acids with a predicted molecular weight of 65 kDa. Structural analysis of the amino acid sequence predicts that the protein has six transmembrane domains, with both the N- and C-termini residing in the cytoplasm. Comparison with the amino acid sequence against known protein motifs and patterns at ProfileScan identified a transient receptor potential (TRP) cation channel domain (amino acids 331–521) and an internal calcium and sodium channel pore region (amino acids 496–521). This TRP domain spans transmembrane segments 3–6, with the putative pore-forming loop between the fifth and sixth segments. Two proline-rich regions were also identified (amino acids 28–36 and 197–205) close to the N-terminus and between the first and second transmembrane segments and a lipase serine active site domain at amino acids 104–114. A leucine zipper motif is located at the second transmembrane domain and a nuclear localization motif at amino acids 43–60 (Fig. 3A). This protein also contains a putative di-leucine motif (L-L-X-X) at the C-terminus which may serve as a late endosomal/lysosomal targeting motif.
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Comparison of the amino acid sequence of mucolipin to GenBank sequences identified the likely Drosophila orthologue, CG8743, and a homologous human unnamed protein product (GenBank accession no. BAA91951) (Fig. 3A). Amino acid sequence identity between mucolipin and the Drosophila gene is striking with 38% identity and nearly perfect conservation of the TRP channel domain and the channel pore region (58% identity). The gene encoding BAA91951 (GenBank accession no. AK001868) is localized to chromosome 1 and the genomic structure was determined by comparison with the cDNA and genomic sequences. Comparison with the cDNA sequences of the two human genes showed that AK001868 does not contain exon 3 of ML4. In order to determine whether this was the result of a splicing difference, we used the amino acid sequence of exon 3 to search GenBank using tblastn. The search was positive for the chromosome 1 genomic clone that contains AK001868 and predicts that exon 3 is probably alternatively spliced in this gene. Exon 3 was included in Figure 3A and shows a similar level of homology with mucolipin and CG8743. Given the high degree of homology between ML4 and BAA91951, we designated the chromosome 1 gene ML4R1.
The Drosophila gene, CG8743, was recently assigned to the polycystin II family within the TRP super-family (10). The TRP cation channel gene family includes proteins that contain six transmembrane domains and are presumed to be Ca2+ transporters activated in a number of signal transduction-related processes (11). Proteins of this family are similar in structure to the family of voltage-dependent calcium and sodium cation channels. A comparison of mucolipin with human polycystin-2 reveals only a limited similarity confined to the TRP channel domain, however, comparison of the hydrophobicity plot of mucolipin with the relevant section of polycystin-2 (amino acids 170–750) demonstrates an overlap of the transmembrane loop structures throughout the proteins (Fig. 3B). Unlike other cation channels, polycystin-2 and mucolipin have a large extracellular loop between the first and second transmembrane domain which probably indicates a similar unique function.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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ML4 encodes a novel protein that shows high similarity to proteins in the TRP channel family. All of the proteins in this family display a topology of six transmembrane segments which is shared with some voltage-gated channels and the cyclic-nucleotide-gated channels. The TRP family is diverse and has been implicated both in calcium entry following receptor activation as well as in calcium entry in specialized cells, specifically epithelial cells (11). To date, >10 TRP family genes have been identified in mammals, including the gene encoding polycystin-2 (PKD2), vanilloid receptor and melastatin. However, with the exception of PKD2, none of them have been implicated in human disease (11). A nearest neighbor dendrogram places the Drosophila homolog of mucolipin, CT25240, as an archeaic member of the TRP channel superfamily in the polycystin II family (10). The predicted sequence of mucolipin is similar to polycystin-2 in the channel motif region (amino acids 361–540) and there is also a high degree of similarity in the hydrophobicity plot between the two proteins. Mucolipin does not contain the long intracellular C- and N-terminal tails characteristic of the presumed activation regions of other cation channels, but rather short tails that may indicate a unique mode of activation. The proline stretches that occur both in the N-terminal region and following the first outer membrane loop, coupled with the lipase motif at amino acid 104, suggest that mucolipin may be activated by lipids. Other TRP channels are also presumed to be activated by lipids that have been released due to the activation of phospholipase C in response to receptor stimulation (12). Since voltage-gated sodium and calcium channels have four linked domains of six transmembrane segments, it has been proposed that TRP channels may function as homo- or heterotetramers of four single subunits (10).
BAA91951 is very similar to mucolipin, however, it lacks the proline-rich domains and the presumed endosomal targeting signal. Rather, BAA91951 has an endoplasmic reticulum targeting motif that may imply a different cellular localization. BAA91951 maps to chromosome 1p22–31 and, to date, no human disease similar to MLIV has been linked to this region. However, given the high degree of homology and the fact that many of the rare lysosomal storage disorders have yet to be mapped, it would not be surprising if it is involved in an MLIV-like disorder.
Mucolipin may have a variety of functions in the cell which are reflected by the general biochemical and clinical aspects of MLIV pathology. The constitutive achlorhydria in MLIV patients and the selective vacuolation in stomach parietal cells of MLIV patients suggests that mucolipin is critical in HCl secretion (5). Similarly, the observed vacuolation in corneal epithelial cells, acinar pancreatic cells, hepatocytes, chondrocytes and renal duct cells (1,13,14) likely indicates dysfunction in ion channel activity and secretion. In the absence of mucolipin activity, inability to proceed with secretion may cause accumulation of solutes in intracellular vesicles and vacuolation. Storage bodies found in other cell types in MLIV, such as neurons and fibroblasts (7,13) may represent high degradation rates of the membranes that would normally contain the mucolipin channel and are destabilized due to its absence. Different phenotypes in different cell types in MLIV indicate that mucolipin may be similar to polycystin-2, which exhibits different subcellular localization and presumably different roles in the various tissues in which it is expressed (15). Moreover, the study of polycystin-2 in primary kidney cell cultures indicates that it is involved in lipid transport toward basolateral membranes (16). Mucolipin may have a similar role, which would account for the abnormality in lipid transport reported in MLIV (17,18). Finally, a reduction in the activity of membrane-bound protein kinase C reported in MLIV (19) suggests that mucolipin participates in signal transduction processes.
Mucolipin deficiency may lead to the sensitivity to chloroquine observed in cultured fibroblasts from MLIV patients (8). This chloroquine sensitivity is possibly related to the role mucolipin would play in the restoration of pH balance to vesicles filled with this weak base. In addition, mucolipin may play a major role in the development of white matter tracts and in the maintenance of neurons and retinal cell integrity as suggested by the pathology and neuro-imaging studies of MLIV patients (3,13).
MLIV is a rare disorder, with 80 cases reported to date (5). However, it is likely that there exists a significant number of MLIV patients who remain unclassified or have been misdiagnosed and therefore the incidence of the disorder is not well documented. With the identification of ML4, there now exists a simple tool for diagnosis and differentiation from the other lysosomal storage disorders. The fact that two mutations account for 96% of all AJ chromosomes makes MLIV amenable to population-based screening. In addition, the observed variability in mutation type and location will permit the study of genotype–phenotype relationships in these patients. Finally, MLIV will be a useful model in which to study the role of a TRP channel gene in brain development and neuronal maintenance, corneal and retinal cellular function and hydrochloric acid secretion.
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MATERIALS AND METHODS |
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MLIV families
Prior to initiating this study, approval from the institutional review boards at Massachusetts General Hospital, Harvard Medical School, the National Institute of Neurological Disorders and Stroke and Hadassah University Hospital was obtained. All patients or their legal guardians signed written informed consent to their participation in the study. We collected samples from 35 AJ and 5 NJ families. We cultured Epstein–Barr virus (EBV) transformed lymphoblasts and primary skin fibroblasts from patients and family members using standard conditions. We prepared genomic DNA and total RNA samples from cultured cells using commercial kits.
Physical mapping
BACs were purchased (Research Genetics, Huntsville, AL) and cosmids were obtained from collaborators at LLNL. Sequence tagged site content mapping, genotyping of MLIV families and haplotype analysis was performed as described (J.S. Aciemo, J.C. Kennedy, J. Falardeau, M.C. Bromley, M. Colman, M. Leyne, M. Sun, C. Bove, L.K. Ashworth, T. Schiripo et al., manuscript in preparation).
Exon trapping
Restriction fragments from BC672420 were shotgun subcloned into the EcoRI site of exon-trapping vector pSPL3 and transfected into COS-7 cells. Spliced products obtained by RT–PCR were cloned into pAMP10 using the UDG cloning kit provided in the exon-trapping system (Life Technologies/Gibco BRL, Rockville, MD) and sequenced.
Full-length ML4 cDNA sequence and mutation analysis
Total RNA from fibroblasts was used for RT–PCR with the following primers designed from the sequence of Image clone 2517653 and GenScan-predicted exons: SM-F3, 5'-CGAGGGAGCGAGGTCGCAGTGACAGC-3' (from exon 1) and SM-R5, 5'-AACACCCTCCCCACCCAGTCTCCCC-3' (from exon 14). The PCR products were cloned into PCR2.1 or TOPO blunt PCR vector (Invitrogen, Carlsbad, CA) and sequenced. The mutation in genomic DNA on the major AJ haplotype patients was analyzed by PCR using primers mg2-EF4 (5'-CAACCTCTACTACCCTCTCCC-3') and mg2-ER4 (5'-AACAGTGAAGCCTCGTCC-3'). The 6434 bp deletion associated with the minor AJ haplotype was identified by using genome walking technology with the Universal Genomewalker kit (Clontech, Palo Alto, CA). The deletion boundaries were confirmed by sequencing purified PCR products generated using the forward primer mg2-GWF4 (5'-CTGATATAAATGGCAGGCAGCTTTC-3') at base pair 226 of the GenBank sequence no. AF287270 and a reverse primer mg2-ER6 (5'-CTCACCGTGCTGGAAGACAC-3') in exon 7 designed according to genome walking results. In order to identify mutations in the unique haplotypes, overlapping sets of PCR primers were designed and used for RT–PCR from lymphoblast or fibroblast RNA. We also designed primers to amplify each exon from genomic DNA. All mutations were confirmed by PCR of genomic DNA and sequencing in the patients and parents (when available).
Northern analysis
Total RNA from fibroblasts or lymphoblasts were used for northern blots. Fifteen micrograms of total RNA was separated by formaldehyde agarose gel electrophoresis, transferred onto a Hybond-N+ nylon membrane (Amersham Pharmacia Biotech, Piscataway, NJ) and UV-cross-linked. The XhoI–EcoRI 2050 bp insert of Image clone 2517653 was random primer labeled with [
-32P]dCTP (Life Technologies/Gibco BRL) and used as a probe on the northern blot for MLIV patients and a human adult multiple-tissue northern blot (Clontech; MTN-I), as well as on a human fetal northern blot (Clontech; MTN Fetal II) to assess tissue distribution. We performed all hybridizations in hybridization solution (0.2 M NaPO4, pH 7.2, 1 mM EDTA, 1% BSA, 7% SDS, 15% formamide) at 65°C overnight. The blots were washed twice in 40 mM NaPO4 pH 7.2, 1% SDS, 1 mM EDTA at 65°C for 30 min.
DNA sequencing
Sequencing was performed using the AmpliCycle sequencing kit (Applied Biosystems, Foster City, CA) or on an ABI 377 automated DNA sequencer at the DNA Sequencing Facility of the National Institutes of Neurological Disorders and Stroke using BigDye terminator cycle sequencing kit (Applied Biosystems).
Bioinformatics
We conducted database searches using BLAST (http://www.ncbi.nlm.nih.gov/blast ). Sequences from UniGene (http://www.ncbi.nlm.nih.gov/UniGene ) were used to confirm the ML4 sequence. We performed motif searches using ProfileScan (http:// www.isrec.isb-sib.ch/software/PFSCAN_form.html and TMPred (http://www.ch.embnet.org/software/TMPRED_form.html ) and alignment of protein sequences using Pileup (GCG) and Boxshade (http://www.ch.embnet.org/softward/BOX_form.html ).
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ACKNOWLEDGEMENTS |
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We thank the patients and families for contributing to this project; Dr R.O. Brady and Dr J. Gusella for useful discussions and critical reading of the manuscript, Linda K. Ashworth from Lawrence Livermore National Laboratory for collaboration on the physical map and Dr G. Bach for supplying MLIV DNA samples. A portion of this work was performed under the auspices of the US Department of Energy at LLNL under contract number W-7405-ENG-48. This work was supported by the ML4 Foundation and a grant from the National Institute of Neurological Disorders and Stroke (RO1-NS39995 to S.A.S.).
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NOTE ADDED IN PROOF |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
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A manuscript supporting our findings was published in September: Bargal et al., Nature Genet., 26, 120–122.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 301 594 3133; Fax: +1 301 496 9480; Email: goldin@codon.nih.gov
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REFERENCES |
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 B. Nilius, G. Owsianik, T. Voets, and J. A. Peters Transient Receptor Potential Cation Channels in Disease Physiol Rev, January 1, 2007; 87(1): 165 - 217. [Abstract] [Full Text] [PDF]
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R. C. Hardie TRP channels and lipids: from Drosophila to mammalian physiology J. Physiol., January 1, 2007; 578(1): 9 - 24. [Abstract] [Full Text] [PDF]
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 L. Schaheen, G. Patton, and H. Fares Suppression of the cup-5 mucolipidosis type IV-related lysosomal dysfunction by the inactivation of an ABC transporter in C. elegans Development, October 1, 2006; 133(19): 3939 - 3948. [Abstract] [Full Text] [PDF]
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M. P. Cuajungco, C. Grimm, K. Oshima, D. D'hoedt, B. Nilius, A. R. Mensenkamp, R. J. M. Bindels, M. Plomann, and S. Heller PACSINs Bind to the TRPV4 Cation Channel: PACSIN 3 MODULATES THE SUBCELLULAR LOCALIZATION OF TRPV4 J. Biol. Chem., July 7, 2006; 281(27): 18753 - 18762. [Abstract] [Full Text] [PDF]
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K. Venkatachalam, T. Hofmann, and C. Montell Lysosomal Localization of TRPML3 Depends on TRPML2 and the Mucolipidosis-associated Protein TRPML1 J. Biol. Chem., June 23, 2006; 281(25): 17517 - 17527. [Abstract] [Full Text] [PDF]
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M. T. Miedel, K. M. Weixel, J. R. Bruns, L. M. Traub, and O. A. Weisz Posttranslational Cleavage and Adaptor Protein Complex-dependent Trafficking of Mucolipin-1 J. Biol. Chem., May 5, 2006; 281(18): 12751 - 12759. [Abstract] [Full Text] [PDF]
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 F. M. Hantash, S. C. Olson, B. Anderson, A. Buller, R. Chen, B. Crossly, W. Sun, and C. M. Strom Rapid One-Step Carrier Detection Assay of Mucolipidosis IV Mutations in the Ashkenazi Jewish Population J. Mol. Diagn., May 1, 2006; 8(2): 282 - 287. [Abstract] [Full Text] [PDF]
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K. Kiselyov, J. Chen, Y. Rbaibi, D. Oberdick, S. Tjon-Kon-Sang, N. Shcheynikov, S. Muallem, and A. Soyombo TRP-ML1 Is a Lysosomal Monovalent Cation Channel That Undergoes Proteolytic Cleavage J. Biol. Chem., December 30, 2005; 280(52): 43218 - 43223. [Abstract] [Full Text] [PDF]
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 D. E. Clapham, D. Julius, C. Montell, and G. Schultz International Union of Pharmacology. XLIX. Nomenclature and Structure-Function Relationships of Transient Receptor Potential Channels Pharmacol. Rev., December 1, 2005; 57(4): 427 - 450. [Full Text] [PDF]
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 C. Montell The TRP Superfamily of Cation Channels Sci. Signal., February 22, 2005; 2005(272): re3 - re3. [Abstract] [Full Text] [PDF]
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 R. Padinjat and S. Andrews TRP channels at a glance J. Cell Sci., November 15, 2004; 117(24): 5707 - 5709. [Full Text] [PDF]
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 C.-L. Huang The Transient Receptor Potential Superfamily of Ion Channels J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1690 - 1699. [Abstract] [Full Text] [PDF]
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 H. F. Cantiello Regulation of calcium signaling by polycystin-2 Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1012 - F1029. [Abstract] [Full Text] [PDF]
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 S. Treusch, S. Knuth, S. A. Slaugenhaupt, E. Goldin, B. D. Grant, and H. Fares Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosome biogenesis PNAS, March 30, 2004; 101(13): 4483 - 4488. [Abstract] [Full Text] [PDF]
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 M. K. Raychowdhury, S. Gonzalez-Perrett, N. Montalbetti, G. A. Timpanaro, B. Chasan, W. H. Goldmann, S. Stahl, A. Cooney, E. Goldin, and H. F. Cantiello Molecular pathophysiology of mucolipidosis type IV: pH dysregulation of the mucolipin-1 cation channel Hum. Mol. Genet., March 15, 2004; 13(6): 617 - 627. [Abstract] [Full Text] [PDF]
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 S. Bonavita, A. Virta, N. Jeffries, E. Goldin, G. Tedeschi, and R. Schiffmann Diffuse Neuroaxonal Involvement in Mucolipidosis IV as Assessed by Proton Magnetic Resonance Spectroscopic Imaging J Child Neurol, July 1, 2003; 18(7): 443 - 449. [Abstract] [PDF]
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K. P. Steel Varitint-waddler: A double whammy for hearing PNAS, November 12, 2002; 99(23): 14613 - 14615. [Full Text] [PDF]
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F. Di Palma, I. A. Belyantseva, H. J. Kim, T. F. Vogt, B. Kachar, and K. Noben-Trauth From the Cover: Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice PNAS, November 12, 2002; 99(23): 14994 - 14999. [Abstract] [Full Text] [PDF]
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 G. Altarescu, M. Sun, D. F. Moore, J. A. Smith, E. A. Wiggs, B. I. Solomon, N. J. Patronas, K. P. Frei, S. Gupta, C. R. Kaneski, et al. The neurogenetics of mucolipidosis type IV Neurology, August 13, 2002; 59(3): 306 - 313. [Abstract] [Full Text] [PDF]
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B. Minke and B. Cook TRP Channel Proteins and Signal Transduction Physiol Rev, April 1, 2002; 82(2): 429 - 472. [Abstract] [Full Text] [PDF]
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 S. M. Pradhan, L.-O. Atchaneeyasakul, B. Appukuttan, R. N. Mixon, T. J. McFarland, A. M. Billingslea, D. J. Wilson, J. T. Stout, and R. G. Weleber Electronegative Electroretinogram in Mucolipidosis IV Arch Ophthalmol, January 1, 2002; 120(1): 45 - 50. [Abstract] [Full Text] [PDF]
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 H. Fares and I. Greenwald Genetic Analysis of Endocytosis in Caenorhabditis elegans: Coelomocyte Uptake Defective Mutants Genetics, September 1, 2001; 159(1): 133 - 145. [Abstract] [Full Text] [PDF]
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C. P. Palmer, X.-L. Zhou, J. Lin, S. H. Loukin, C. Kung, and Y. Saimi |