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• W2048997930 abstract "Night vision requires signaling from rod photoreceptors to adjacent bipolar cells in the retina. Mutations in the genes NYX and GRM6, expressed in ON bipolar cells, lead to a disruption of the ON bipolar cell response. This dysfunction is present in patients with complete X-linked and autosomal-recessive congenital stationary night blindness (CSNB) and can be assessed by standard full-field electroretinography (ERG), showing severely reduced rod b-wave amplitude and slightly altered cone responses. Although many cases of complete CSNB (cCSNB) are caused by mutations in NYX and GRM6, in ∼60% of the patients the gene defect remains unknown. Animal models of human diseases are a good source for candidate genes, and we noted that a cCSNB phenotype present in homozygous Appaloosa horses is associated with downregulation of TRPM1. TRPM1, belonging to the family of transient receptor potential channels, is expressed in ON bipolar cells and therefore qualifies as an excellent candidate. Indeed, mutation analysis of 38 patients with CSNB identified ten unrelated cCSNB patients with 14 different mutations in this gene. The mutation spectrum comprises missense, splice-site, deletion, and nonsense mutations. We propose that the cCSNB phenotype in these patients is due to the absence of functional TRPM1 in retinal ON bipolar cells. Night vision requires signaling from rod photoreceptors to adjacent bipolar cells in the retina. Mutations in the genes NYX and GRM6, expressed in ON bipolar cells, lead to a disruption of the ON bipolar cell response. This dysfunction is present in patients with complete X-linked and autosomal-recessive congenital stationary night blindness (CSNB) and can be assessed by standard full-field electroretinography (ERG), showing severely reduced rod b-wave amplitude and slightly altered cone responses. Although many cases of complete CSNB (cCSNB) are caused by mutations in NYX and GRM6, in ∼60% of the patients the gene defect remains unknown. Animal models of human diseases are a good source for candidate genes, and we noted that a cCSNB phenotype present in homozygous Appaloosa horses is associated with downregulation of TRPM1. TRPM1, belonging to the family of transient receptor potential channels, is expressed in ON bipolar cells and therefore qualifies as an excellent candidate. Indeed, mutation analysis of 38 patients with CSNB identified ten unrelated cCSNB patients with 14 different mutations in this gene. The mutation spectrum comprises missense, splice-site, deletion, and nonsense mutations. We propose that the cCSNB phenotype in these patients is due to the absence of functional TRPM1 in retinal ON bipolar cells. Congenital stationary night blindness (CSNB) is a group of genetically and clinically heterogeneous retinal disorders. The genes involved in the different forms of CSNB encode proteins, which are confined to the phototransduction cascade or are important in retinal signaling from photoreceptors to adjacent bipolar cells.1Zeitz C. Molecular genetics and protein function involved in nocturnal vision.Expert Rev Ophthalmol. 2007; 2: 467-485Crossref Scopus (37) Google Scholar Most of the patients with mutations in these genes show a typical electrophysiological phenotype characterized by an electronegative waveform of the dark-adapted, bright-flash electroretinogram (ERG), in which the amplitude of the b-wave is smaller than that of the a-wave.2Schubert G. Bornschein H. Ophthalmologica. 1952; 123: 396-413Crossref PubMed Scopus (154) Google Scholar This so-called Schubert-Bornschein type of ERG response allows the discrimination of two subtypes of CSNB: incomplete (ic) (CSNB2A [MIM 300071], CSNB2B [MIM 610427]) and complete (c) (CSNB1A [MIM 310500], CSNB1B [MIM 257270].3Miyake Y. Yagasaki K. Horiguchi M. Kawase Y. Kanda T. Congenital stationary night blindness with negative electroretinogram. A new classification.Arch. Ophthalmol. 1986; 104: 1013-1020Crossref PubMed Scopus (360) Google Scholar The incomplete type is characterized by both a reduced rod b-wave and substantially reduced cone response, due to both ON and OFF bipolar cell dysfunction, whereas the complete type is associated with a drastically reduced rod b-wave response but largely normal cone b-wave amplitudes, due to ON bipolar cell dysfunction.4Audo I. Robson A.G. Holder G.E. Moore A.T. The negative ERG: clinical phenotypes and disease mechanisms of inner retinal dysfunction.Surv. Ophthalmol. 2008; 53: 16-40Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar In a considerable fraction of CSNB patients, mutations have been identified by direct sequencing of candidate genes or microarray analysis.5Zeitz C. Labs S. Lorenz B. Forster U. Ueksti J. Kroes H.Y. De Baere E. Leroy B.P. Cremers F.P. Wittmer M. et al.Genotyping microarray for CSNB-associated genes.Invest Ophthalmol Vis Sci. 2009; (Published online July 2, 2009)Google Scholar However, from our CSNB cohort, the phenotype in ∼60% of the patients could not be associated with mutations in known genes, indicating that additional genes remain unidentified. Recently, a type of CSNB in Appaloosa horses has been described.6Sandmeyer L.S. Breaux C.B. Archer S. Grahn B.H. Clinical and electroretinographic characteristics of congenital stationary night blindness in the Appaloosa and the association with the leopard complex.Vet. Ophthalmol. 2007; 10: 368-375Crossref PubMed Scopus (53) Google Scholar, 7Witzel D.A. Smith E.L. Wilson R.D. Aguirre G.D. Congenital stationary night blindness: an animal model.Invest. Ophthalmol. Vis. Sci. 1978; 17: 788-795PubMed Google Scholar Affected animals initially showed reduced vision in dim light conditions, which subsequently progressed to reduced vision even in normal light conditions in severely affected animals. No fundus abnormalities were present, but strabismus and nystagmus were described. Electrophysiological studies revealed a “negative ERG” resembling the human Schubert-Bornschein type of ERG response.8Sandmeyer L.S. Grahn B.H. Breaux C.B. Diagnostic ophthalmology. Congenital stationary night blindness (CSNB).Can Vet J. 2006; 47: 1131-1133PubMed Google Scholar Furthermore, the photopic flicker responses of affected horses seemed to be similar when compared with those of unaffected horses,6Sandmeyer L.S. Breaux C.B. Archer S. Grahn B.H. Clinical and electroretinographic characteristics of congenital stationary night blindness in the Appaloosa and the association with the leopard complex.Vet. Ophthalmol. 2007; 10: 368-375Crossref PubMed Scopus (53) Google Scholar suggesting a phenotype reminiscent of cCSNB. Association studies of the coat coloring in these horses revealed that this trait is directly linked with the CSNB phenotype. Gene expression analysis of genes linked to this disorder revealed that TRPM1 (MIM 603576), also known as melastatin (MLSN1), was significantly downregulated in the retina and skin of affected animals. Thus, it was proposed that TRPM1 is responsible for altering bipolar signaling as well as melanocyte function, causing both CSNB and the coat color phenotype in Appaloosa horses.9Bellone R.R. Brooks S.A. Sandmeyer L. Murphy B.A. Forsyth G. Archer S. Bailey E. Grahn B. Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus).Genetics. 2008; 179: 1861-1870Crossref PubMed Scopus (120) Google Scholar Studies in mice lacking Trpm1 revealed a severely reduced b-wave in ERG recordings, similar to the Schubert-Bornschein type of ERG response.10Shen Y. Heimel J.A. Kamermans M. Peachey N.S. Gregg R.G. Nawy S. A transient receptor potential-like channel mediates synaptic transmission in rod bipolar cells.J. Neurosci. 2009; 29: 6088-6093Crossref PubMed Scopus (156) Google Scholar These findings support the hypothesis that this gene is important for night vision. TRPM1 is a member of the transient receptor potential (TRP) channel family. These channels permit Ca2+ entry into hyperpolarized cells, producing intracellular responses linked to the phosphatidylinositol and protein kinase C signal transduction pathway.11Clapham D.E. Runnels L.W. Strubing C. The TRP ion channel family.Nat. Rev. Neurosci. 2001; 2: 387-396Crossref PubMed Scopus (905) Google Scholar Because of the downregulation of TRPM1 in Appaloosa horses with CSNB, it was suggested that this gene may play a role in neural transmission in the human retina through changing cytosolic-free Ca2+ levels in the retina in ON bipolar cells. The mGluR6 protein (MIM 604096) of the ON bipolar cells is coupled to Gαo proteins (MIM 139311) and to TRPM1. TRPM1 might be the cation channel that is downstream of the Gαo protein in the ON bipolar cells.9Bellone R.R. Brooks S.A. Sandmeyer L. Murphy B.A. Forsyth G. Archer S. Bailey E. Grahn B. Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus).Genetics. 2008; 179: 1861-1870Crossref PubMed Scopus (120) Google Scholar Altogether, the phenotype of Appaloosa horses, the downregulation of TRPM1 in affected animals, and its localization downstream of mGluR6 in ON bipolar cells rendered this gene a good candidate. Thus, we screened this gene in 38 clinically diagnosed CSNB patients from different centers in Europe and the United States (Belgium: Ghent; France: Paris, Montpellier, and Lille; Germany: Berlin, Freiburg, Giessen, and Tuebingen; Switzerland: Lausanne; United States: Philadelphia, PA). Prior to this study, most patients were excluded either for known mutations, by a CSNB genotyping microarray, or for known CSNB genes and additional candidate genes, by direct sequencing.5Zeitz C. Labs S. Lorenz B. Forster U. Ueksti J. Kroes H.Y. De Baere E. Leroy B.P. Cremers F.P. Wittmer M. et al.Genotyping microarray for CSNB-associated genes.Invest Ophthalmol Vis Sci. 2009; (Published online July 2, 2009)Google Scholar Research procedures were conducted in accordance with institutional guidelines and the Declaration of Helsinki. Prior to genetic testing, informed consent was obtained from all patients and their family members. Ophthalmic examination included best corrected visual acuity, slit lamp examination, funduscopy, Goldmann kinetic perimetry, full-field ERG incorporating the ISCEV (International Society for Clinical Electrophysiology of Vision) standards,12Marmor M.F. Fulton A.B. Holder G.E. Miyake Y. Brigell M. Bach M. ISCEV Standard for full-field clinical electroretinography (2008 update).Doc. Ophthalmol. 2009; 118: 69-77Crossref PubMed Scopus (805) Google Scholar fundus autofluorescence, and optical coherence tomography (OCT) (extent of investigation depending on the referring center). Thirty fragments covering 27 exons of TRPM1 (RefSeq NM_002420.4, variant 70+TRPM113Oancea E. Vriens J. Brauchi S. Jun J. Splawski I. Clapham D.E. TRPM1 forms ion channels associated with melanin content in melanocytes.Sci Signal. 2009; 2: ra21PubMed Google Scholar), two fragments corresponding to two recently identified exons (exon 1′ [variant 92+TRPM113Oancea E. Vriens J. Brauchi S. Jun J. Splawski I. Clapham D.E. TRPM1 forms ion channels associated with melanin content in melanocytes.Sci Signal. 2009; 2: ra21PubMed Google Scholar] and exon 0 [variant 109+TRPM113Oancea E. Vriens J. Brauchi S. Jun J. Splawski I. Clapham D.E. TRPM1 forms ion channels associated with melanin content in melanocytes.Sci Signal. 2009; 2: ra21PubMed Google Scholar]) of this gene (Figure 1), and the flanking intronic regions were directly sequenced from the PCR-amplified products (primers are listed in Table S1, available online) with the use of a sequencing mix (BigDye Terminator v1.1 Cycle Sequencing Kit, Applied Biosystems, Courtabœuf, France) and analyzed on an automated 48-capillary sequencer (ABI 3730 Genetic Analyzer, Applied Biosystems). The results were interpreted by a software application (SeqScape, Applied Biosystems). Analysis in TRPM1 revealed causative mutations in ten cCSNB patients (Figure 2: patient CIC00238 shown as an example of cCSNB) with a total of 14 different mutations (Figure 1 and Table 1). These comprise nonsense mutations, a deletion leading to a predicted premature stop codon, splice-site mutations, silent mutations, and missense mutations. None of these changes were found among control chromosomes (210–380 chromosomes). In those patients from whom family members could be investigated, the cCSNB phenotype cosegregated with the mutations and the genotypes were indicative for autosomal-recessive inheritance (Figures 3A and 3B: three patient examples). Five index patients (4497, 8214, CIC00612, 23625, and 758) showed compound heterozygous mutations (Table 1). Patients CIC00612 and 23625 both revealed a heterozygous p.Tyr72Cys substitution. From the origins of these patients, no close familial relationship was obvious. In three index patients (CIC00238, 691, and D0704708), an apparently homozygous mutation was found (Table 1). Homozygosity was proven for index patient D0704708 (Figure 3). Cosegregation analysis from family members of index patient CIC00238 revealed that another affected sister was apparently homozygous for the mutation, whereas the father was heterozygous. Two unaffected sisters and, interestingly, the mother did not show the mutation (Table 1). These findings indicated that the patient is most likely heterozygous for the missense mutation inherited from the father and would have a deletion in TRPM1 or a mutation in another gene, which would have been inherited from the mother. Four investigated SNPs (rs4779818 in intron 1, rs4779816 in exon 2, rs2241493 in exon 3, and rs2288242 in exon 18) were apparently homozygous in the patient and the parents. Therefore, the putative deletion could not be defined. Analyses of additional SNPs in genomic regions of TRPM1 or screening of candidate genes may enable us to localize the second mutation and will be investigated in the future. The parents of patient 691 were not available for genetic testing, and thus homozygosity could not be proven. For two patients, 14101 and 10731, only one heterozygous mutation was identified (Table 1). Again, the second mutation may be a large heterozygous deletion and thus not detectable by PCR-based sequencing. In addition, a mutation located in a second gene may disable signaling important for nocturnal vision. Three investigated SNPs (rs4779816 in exon 2, rs2241493 in exon 3, and rs3782599 in exon 4) were apparently homozygous in the patient and the parents, and thus the putative deletion could not be defined. Mutation analysis in patient 14101 on other known or candidate genes (NYX, AJ278865 [MIM 300278]; GRM6, NM_000843; CABP4, NM_145200 [MIM 608965]; CACNA2D4, NM_172364 [MIM 608171]; BHLHB4, BK000274 [MIM 609331]; CACN2B, NM_000724 [MIM 600003]; GNA01, NM_020988 and NM_138736; and TBC1D2, NM_018421 [MIM 609871]) did not reveal any mutation. Previous mutation analyses in the simplex case 10731 in known and candidate genes (NYX, CACNA1F, AJ006216 [MIM 300110], GRM6, CABP4, CACNA2D4, BHLHB4, CACN2B, GNA01, and TBC1D2) did not reveal any mutation. Thus, for both patients, the second mutation may be found in other regions of TRPM1, such as regulatory sequences or unidentified exons, or may represent a deletion in an as-yet-uninvestigated region of TRPM1. Alternatively, the second mutation may be found in a novel CSNB gene.Table 1Patients with Likely Pathogenic TRPM1 MutationsIndex Patient, Location, Family MembersEthnicityExonNucleotide ExchangeAllele StateProtein EffectControl Alleles (Mut/WT)Phenotype IndexCIC00238: Paris, FrancePortuguese-French12c.1418G>Chom?p.Arg473Pro0/286cCSNB, myopia, nystagmus, strabismusunaff. father CIC0342412c.1418G>Chetp.Arg473Prounaff. mother CIC03423-no--unaff. sister CIC03421-no--unaff. sister CIC03422-no--aff. sister CIC0345212c.1418G>Chom?p.Arg473ProcCSNB, myopia, nystagmus, strabismus4497aSee Figures 3A and 3B., II-1: Tuebingen, GermanyGerman3c.31C>Thetp.Gln11X0/352cCSNB, nystagmus, myopia4c.296T>Chetp.Leu99Pro0/224unaff. father 4608, I-14c.296T>Chetp.Leu99Prounaff. mother 4610, I-23c.31C>Thetp.Gln11Xunaff. sister 4600, II-2-no--unaff. sister 4712, II-43c.31C>Thetp.Gln11Xunaff. brother 4740, II-33c.31C>Thetp.Gln11X691: Tuebingen, GermanyTurkish20c.2567G>Ahom?p.Trp856X0/366cCSNB, myopia, nystagmus,strabismus8214: Tuebingen, GermanyGerman10c.1197G>Ahetc.Pro399Pro/splice defect?0/350cCSNB, myopia, strabismus26c.3491delAhetp.Gln1164ArgfsX310/266CIC00612: Paris, FranceFrench4c.215A>Ghetp.Tyr72Cys0/210cCSNB, myopia, nystagmus, strabismus24c.3094G>Thetp.Glu1032X0/370unaff. mother: CIC0335924c.3094G>Thetp.Glu1032Xunaff. brother: CIC03360-no--23625aSee Figures 3A and 3B., II-3: Lausanne, SwitzerlandItalian4c.215A>Ghetp.Tyr72Cys0/210cCSNB, myopiaint4c.428-3C>Ghetsplice defect0/298unaff. father 23628, I-14c.215A>Ghetp.Tyr72Cysunaff. mother 23728, I-2int4c.428-3C>Ghetsplice defectunaff. brother CIC03365, II-1-no-unaff. brother CIC03364, II-24c.215A>Ghetp.Tyr72Cys758.01: Giessen, GermanyGermanint20c.2634+1G>Ahetsplice defect0/366cCSNB27c.3834C>Thetp.Asn1278Asn0/304D0704708aSee Figures 3A and 3B., II-3: Ghent, Belgiumb27533 Diagnostic: Zurich, Switzerland.Flemish-Belgian2c.1-27C>T (70+TRPM1) or c.40C>T (92+TRPM1)hom5′ UTR expression defect or p.Arg14Trp0/348cCSNB, strabismus, hypermetropiaunaff. father CIC03386, I-12″het5′ UTR expression defect or p.Arg14Trpunaff. mother D0704709, I-22″het5′ UTR expression defect or p.Arg14Trpunaff. sister CIC03389, II-12″het5′ UTR expression defect or p.Arg14Trpunaff. sister CIC03390, II-22″het5′ UTR expression defect or p.Arg14Trpunaff. brother CIC03391, II-3-no-14101: Philadelphia, PA, USAAustrian-Russian-Ashkenazi Jewish18c.2322T>Ahetp.Tyr774X0/380cCSNB, myopia??-?unaff. father 19037??-?unaff. mother 1903818c.2322T>Ahetp.Tyr774X10731: Berlin, GermanyGerman14c.1622T>Ahetp.Met541Lys0/214cCSNB, myopia??-?Index patients are presented in bold. Abbreviations are as follows: Mut, mutated; het, heterozygous; hom, homozygous; unaff., unaffected; aff., affected. CSNB mutations are annotated according to the recommendation of the Human Genome Variation Society, with nucleotide position +1 corresponding to the A of the translation-initiation codon ATG in the cDNA nomenclature RefSeq NM_002420.4, 70+TRPM1. For Exon 0 and Exon 1′, the respective A of the new translation initiation codon ATG was used.a See Figures 3A and 3B.b 27533 Diagnostic: Zurich, Switzerland. Open table in a new tab Figure 3TRPM1 Mutations and Cosegregation Analysis in Families with CSNBShow full caption(A) Electropherograms of three index patients provided as an example, showing TRPM1 mutations, which are highlighted by an arrow. Exonic sequence is shown in capital letters. Intronic sequence is shown in lowercase letters.(B) Corresponding pedigrees of selected cCSNB patients with TRPM1 mutations and cosegregation in available family members. Filled symbols represent affected individuals, and unfilled symbols represent unaffected persons. Squares indicate males, and circles indicate females. Arrows reflect the index patients.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Index patients are presented in bold. Abbreviations are as follows: Mut, mutated; het, heterozygous; hom, homozygous; unaff., unaffected; aff., affected. CSNB mutations are annotated according to the recommendation of the Human Genome Variation Society, with nucleotide position +1 corresponding to the A of the translation-initiation codon ATG in the cDNA nomenclature RefSeq NM_002420.4, 70+TRPM1. For Exon 0 and Exon 1′, the respective A of the new translation initiation codon ATG was used. (A) Electropherograms of three index patients provided as an example, showing TRPM1 mutations, which are highlighted by an arrow. Exonic sequence is shown in capital letters. Intronic sequence is shown in lowercase letters. (B) Corresponding pedigrees of selected cCSNB patients with TRPM1 mutations and cosegregation in available family members. Filled symbols represent affected individuals, and unfilled symbols represent unaffected persons. Squares indicate males, and circles indicate females. Arrows reflect the index patients. One other patient (13830) with icCSNB was compound heterozygous for two missense changes: c.1195C>A, causing a p.Pro399Thr substitution in exon 10, and c.3483G>C, leading to a p.Gln1161His substitution in exon 26, respectively (Table 2). However, the c.1195C>A change was found in eight of 350 control chromosomes and the c.3483G>C in two of 266. Thus, both variants are most likely non-disease-causing variants. This is also consistent with the fact that TRPM1 mutations in our study specifically lead to cCSNB and not to icCSNB. Another variant (c.4123G>T) in exon 27, leading to a p.Glu1375X, was detected in three patients but turned out to be a SNP (rs378489), which was detected in 20 of 320 control chromosomes. Other presumably non-disease-causing variants were detected and are summarized in Table 3.Table 2Likely Non-Disease-Causing TRPM1 Variants Identified in Patients with CSNBExonNucleotide ExchangeAllele StateProtein EffectControl Alleles (Mut/WT)Conclusion0c.16C>Thet or homp.Arg6Trpfrequent in patients and controlsnew, but T occurs also in Platypus; thus, SNP10c.1195C>Ahetp.Pro399Thr8/350SNP26c.3483G>Chetp.Gln1161His2/266SNP27c.4123G>Thetp.Glu1375X20/320SNPc.4264C>Thet or homp.Arg1422Trpfrequent in patients and controlsnew, but 2/334 alleles showed exchange; thus, SNPAbbreviations are as follows: Mut, mutated; het, heterozygous; hom, homozygous. CSNB mutations are annotated according to the recommendation of the Human Genome Variation Society, with nucleotide position +1 corresponding to the A of the translation-initiation codon ATG in the cDNA nomenclature RefSeq NM_002420.4, 70+TRPM1. For Exon 0 and Exon 1′, the respective A of the new translation initiation codon ATG was used. Open table in a new tab Table 3Benign TRPM1 Variants Identified in CSNB PatientsExonNucleotide ExchangeProtein EffectSNP ID2c.2T>Cp.Met1Thrrs47798163c.95G>Ap.Ser32Asnrs224149311c.1239G>Ap.Thr413Thrrs103570516c.1813G>Ap.Val605Metrs1781577418c.2307T>Cp.Tyr769Tyrrs12913672c.2340T>Cp.Asn780Asnrs228824219c.2475C>Tp.Asn825Asnrs1291135027c.3686A>Cp.Asn1229Thrrs17227996c.4135C>Ap.Pro1379Thrrs61734298c.4139G>Ap.Val1395Ilers3784588c.4494T>Ap.His1483Glnrs12898290CSNB mutations are annotated according to the recommendation of the Human Genome Variation Society, with nucleotide position +1 corresponding to the A of the translation-initiation codon ATG in the cDNA nomenclature RefSeq NM_002420.4, 70+TRPM1. Open table in a new tab Abbreviations are as follows: Mut, mutated; het, heterozygous; hom, homozygous. CSNB mutations are annotated according to the recommendation of the Human Genome Variation Society, with nucleotide position +1 corresponding to the A of the translation-initiation codon ATG in the cDNA nomenclature RefSeq NM_002420.4, 70+TRPM1. For Exon 0 and Exon 1′, the respective A of the new translation initiation codon ATG was used. CSNB mutations are annotated according to the recommendation of the Human Genome Variation Society, with nucleotide position +1 corresponding to the A of the translation-initiation codon ATG in the cDNA nomenclature RefSeq NM_002420.4, 70+TRPM1. The most likely pathogenic mutations identified herein were predicted to localize at different sites of the TRP channel. Five missense mutations, which were found in evolutionarily conserved residues (Figure 4), one silent mutation, and one nonsense mutation were predicted to localize in the N-terminal intracellular part of TRPM1 (Figure 5), the function of which is not yet understood.11Clapham D.E. Runnels L.W. Strubing C. The TRP ion channel family.Nat. Rev. Neurosci. 2001; 2: 387-396Crossref PubMed Scopus (905) Google Scholar All missense mutations were predicted by homology-based programs (SIFT amd Polyphen, data not shown) to be pathogenic. Another silent mutation was identified in the C terminus of TRPM1. For all of these, in addition to the splice-site mutations, splicing could be influenced because different splicing proteins were predicted to bind to the mutated variants in comparison to the control (ESEfinder, data not shown). In addition, mislocalization of the mutated proteins or channel-gating defects could be the underlying pathogenic mechanisms leading to cCSNB. In total, five different mutations, predicted to lead to premature-termination codons in different locations of the protein, were identified. We assume that the corresponding mutant mRNAs of these alleles would probably be subjected to nonsense-mediated decay or produce a short nonfunctional form of TRPM1. Previous studies showed that a shorter, alternatively spliced N-terminal form of TRPM1 devoid of any putative transmembrane segments (amino acids ∼1–500) can directly interact and suppress the activity of the full-length form by preventing its translocation to the plasma membrane and thus inhibiting Ca2+ entry into the cell.14Xu X.Z. Moebius F. Gill D.L. Montell C. Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.Proc. Natl. Acad. Sci. USA. 2001; 98: 10692-10697Crossref PubMed Scopus (177) Google Scholar It was suggested that under normal conditions, this mechanism regulates the exact amount of molecules necessary for proper channel function.Figure 5Localization of TRPM1 Mutations with Respect to Predicted Channel DomainsShow full captionThe specific domains for the TRPM1 channel were estimated by the use of different publications and prediction programs14Xu X.Z. Moebius F. Gill D.L. Montell C. Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.Proc. Natl. Acad. Sci. USA. 2001; 98: 10692-10697Crossref PubMed Scopus (177) Google Scholar, 32Fang D. Setaluri V. Expression and Up-regulation of alternatively spliced transcripts of melastatin, a melanoma metastasis-related gene, in human melanoma cells.Biochem. Biophys. Res. Commun. 2000; 279: 53-61Crossref PubMed Scopus (74) Google Scholar (UniProtKB-Swiss-Prot).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The specific domains for the TRPM1 channel were estimated by the use of different publications and prediction programs14Xu X.Z. Moebius F. Gill D.L. Montell C. Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.Proc. Natl. Acad. Sci. USA. 2001; 98: 10692-10697Crossref PubMed Scopus (177) Google Scholar, 32Fang D. Setaluri V. Expression and Up-regulation of alternatively spliced transcripts of melastatin, a melanoma metastasis-related gene, in human melanoma cells.Biochem. Biophys. Res. Commun. 2000; 279: 53-61Crossref PubMed Scopus (74) Google Scholar (UniProtKB-Swiss-Prot). Currently, there are two genes implicated in complete CSNB: NYX and GRM6.15Zeitz C. van Genderen M. Neidhardt J. Luhmann U.F. Hoeben F. Forster U. Wycisk K. Matyas G. Hoyng C.B. Riemslag F. et al.Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram.Invest. Ophthalmol. Vis. Sci. 2005; 46: 4328-4335Crossref PubMed Scopus (110) Google Scholar, 16Bech-Hansen N.T. Naylor M.J. Maybaum T.A. Sparkes R.L. Koop B. Birch D.G. Bergen A.A. Prinsen C.F. Polomeno R.C. Gal A. et al.Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness.Nat. Genet. 2000; 26: 319-323Crossref PubMed Scopus (263) Google Scholar, 17Pusch C.M. Zeitz C. Brandau O. Pesch K. Achatz H. Feil S. Scharfe C. Maurer J. Jacobi F.K. Pinckers A. et al.The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein.Nat. Genet. 2000; 26: 324-327Crossref PubMed Scopus (198) Google Scholar, 18Dryja T.P. McGee T.L. Berson E.L. Fishman G.A. Sandberg M.A. Alexander K.R. Derlacki D.J. Rajagopalan A.S. Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6.Proc. Natl. Acad. Sci. USA. 2005; 102: 4884-4889Crossref PubMed Scopus (181) Google Scholar They code for the proteins nyctalopin and mGluR6, respectively, which localize postsynaptically to the photoreceptors in the retina in ON bipolar cells.19Morgans C.W. Ren G. Akileswaran L. Localization of nyctalopin in the mammalian retina.Eur. J. Neurosci. 2006; 23: 1163-1171Crossref PubMed Scopus (56) Google Scholar Whereas the function of nyctalopin is not yet understood, mGluR6 was shown to be important for the glutamate uptake released from the photoreceptors (Figure 6). The most obvious phenotypical feature of patients with cCSNB is a defect of the ON response, resulting in an electronegative combined rod-cone ERG, based on a severely reduced b-wave.2Schubert G. Bornschein H. Ophthalmologica. 1952; 123: 396-413Crossref PubMed Scopus (154) Google Scholar In the dark, glutamate is released from photoreceptors, binds to mGluR6, and activates the Gαo1 subunit of a heterotrimeric G protein. This in turn leads by an unidentified mechanism to the closure of an as-yet-unknown cation channel (Figure 6).1Zeitz C. Molecular genetics and protein function involved in nocturnal vision.Expert Rev Ophthalmol. 2007; 2: 467-485Crossref Scopus (37) Google Scholar, 20Nomura A. Shigemoto R. Nakamura Y. Okamoto N. Mizuno N. Nakanishi S. Developmentally regulated postsynaptic localization of a metabotropic glutamate receptor in rat rod bipolar cells.Cell. 1994; 77: 361-369Abstract Full Text PDF PubMed Scopus (364) Google Scholar, 21Vardi N. Morigiwa K. ON cone bipolar cells in rat express the metabotropic receptor mGluR6.Vis. Neurosci. 1997; 14: 789-794Crossref PubMed Scopus (109) Google Scholar, 22Vardi N. Duvoisin R. Wu G. Sterling P. Localization of mGluR6 to dendrites of ON bipolar cells in primate retina.J. Comp. Neurol. 2000; 423: 402-412Crossref PubMed Scopus (168) Google Scholar, 23Nawy S. The metabotropic receptor mGluR6 may signal through G(o), but not phosphodiesterase, in retinal bipolar cells.J. Neurosci. 1999; 19: 2938-2944PubMed Google Scholar, 24Dhingra A. Lyubarsky A. Jiang M. Pugh Jr., E.N. Birnbaumer L. Sterling P. Vardi N. The light response of ON bipolar neurons requires G[alpha]o.J. Neurosci. 2000; 20: 9053-9058PubMed Google Scholar, 25Dhingra A. Jiang M. Wang T.L. Lyubarsky A. Savchenko A. Bar-Yehuda T. Sterling P. Birnbaumer L. Vardi N. Light response of retinal ON bipolar cells requires a specific splice variant of Galpha(o).J. Neurosci. 2002; 22: 4878-4884Crossref PubMed Google Scholar Upon light exposure, photoreceptor glutamate release decreases and the ON response is initiated with the shutting down of the G protein cascade. Subsequently, the cation channel opens, leading to ON bipolar cell depolarization, giving rise to the b-wave. Mutations in GRM6 lead to the loss of mGluR6 at the cell surface. Modulation of glutamate released from the photoreceptors cannot be correctly sensed by the bipolar cells, resulting in the failure of depolarization and thus a severely reduced b-wave.26Zeitz C. Forster U. Neidhardt J. Feil S. Kalin S. Leifert D. Flor P.J. Berger W. Night blindness-associated mutations in the ligand-binding, cysteine-rich, and intracellular domains of the metabotropic glutamate receptor 6 abolish protein trafficking.Hum. Mutat. 2007; 28: 771-780Crossref PubMed Scopus (48) Google Scholar Recent findings in Appaloosa horses with CSNB and a specific coat patterning caused by low expression of a TRP channel, Trpm1, suggested that this specific channel is specifically linked to the depolarization of the ON bipolar cells during light exposure. However, no direct sequencing of the Trpm1 gene was performed in the horse, and thus the loss of ON bipolar cell function could rather be due to a secondary effect than to the mutated Trpm1. Nevertheless, mice lacking this channel showed the same ocular phenotype with a severely reduced b-wave.10Shen Y. Heimel J.A. Kamermans M. Peachey N.S. Gregg R.G. Nawy S. A transient receptor potential-like channel mediates synaptic transmission in rod bipolar cells.J. Neurosci. 2009; 29: 6088-6093Crossref PubMed Scopus (156) Google Scholar Together these findings indicated that mutations in this gene could be responsible for CSNB in patients, and indeed, our study presented herein revealed 14 different mutations in TRPM1 in ten different families with autosomal-recessive cCSNB. Patients carrying mutations in TRPM1 reveal a similar ocular phenotype. All showed cCSNB with selective dysfunction of the ON bipolar pathway and OFF bipolar pathway preservation. Most of them revealed at least one of the following additional ocular abnormalities: myopia, nystagmus, or strabismus. These clinical observations are in accordance with the phenotype observed in the night-blind Appaloosa horses also showing nystagmus and strabismus. Although Bellone et al. showed downregulation of Trpm1 in these horses,9Bellone R.R. Brooks S.A. Sandmeyer L. Murphy B.A. Forsyth G. Archer S. Bailey E. Grahn B. Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus).Genetics. 2008; 179: 1861-1870Crossref PubMed Scopus (120) Google Scholar it will be interesting to see which mutations in Trpm1 lead to its downregulation. Because of the fact that the ocular phenotype was similar in all patients and because of the presence of a large fraction of nonsense and splice-site mutations, we hypothesize that this form of autosomal-recessive cCSNB is due to a lack of TRPM1 mRNA or functional TRPM1 protein on the surface, rather than to functional alterations in the biophysical properties of this channel. The study of animal models carrying the identified mutations and investigation of transcript in the retina are needed for verification of this hypothesis. To date, three genes have been associated with icCSNB (CACNA1F, CABP4, and CACNA2D4),27Bech-Hansen N.T. Naylor M.J. Maybaum T.A. Pearce W.G. Koop B. Fishman G.A. Mets M. Musarella M.A. Boycott K.M. Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness.Nat. Genet. 1998; 19: 264-267Crossref PubMed Scopus (401) Google Scholar, 28Strom T.M. Nyakatura G. Apfelstedt-Sylla E. Hellebrand H. Lorenz B. Weber B.H. Wutz K. Gutwillinger N. Ruther K. Drescher B. et al.An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness.Nat. Genet. 1998; 19: 260-263Crossref PubMed Scopus (373) Google Scholar, 29Zeitz C. Kloeckener-Gruissem B. Forster U. Gebhart M. Magyar I. Mátyás G. Striessnig J. Berger B. Mutations in the calcium-binding protein 4 (CABP4) cause autosomal recessive night blindness.Invest. Ophthalmol. Vis. Sci. 2007; 49 (E-Abstract 6085.)Google Scholar, 30Wycisk K.A. Zeitz C. Feil S. Wittmer M. Forster U. Neidhardt J. Wissinger B. Zrenner E. Wilke R. Kohl S. et al.Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy.Am. J. Hum. Genet. 2006; 79: 973-977Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar and with the findings now reported here, there are also three genes associated with cCSNB (NYX, GRM6, and TRPM1)15Zeitz C. van Genderen M. Neidhardt J. Luhmann U.F. Hoeben F. Forster U. Wycisk K. Matyas G. Hoyng C.B. Riemslag F. et al.Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram.Invest. Ophthalmol. Vis. Sci. 2005; 46: 4328-4335Crossref PubMed Scopus (110) Google Scholar, 16Bech-Hansen N.T. Naylor M.J. Maybaum T.A. Sparkes R.L. Koop B. Birch D.G. Bergen A.A. Prinsen C.F. Polomeno R.C. Gal A. et al.Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness.Nat. Genet. 2000; 26: 319-323Crossref PubMed Scopus (263) Google Scholar, 17Pusch C.M. Zeitz C. Brandau O. Pesch K. Achatz H. Feil S. Scharfe C. Maurer J. Jacobi F.K. Pinckers A. et al.The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein.Nat. Genet. 2000; 26: 324-327Crossref PubMed Scopus (198) Google Scholar, 18Dryja T.P. McGee T.L. Berson E.L. Fishman G.A. Sandberg M.A. Alexander K.R. Derlacki D.J. Rajagopalan A.S. Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6.Proc. Natl. Acad. Sci. USA. 2005; 102: 4884-4889Crossref PubMed Scopus (181) Google Scholar (Figure 7). With respect to the other autosomal-recessive CSNB genes identified so far, TRPM1 seems to be the most frequently mutated gene. The authors are grateful to the families described in this study, to Dominique Santiard-Baron and Christine Chaumeil for their help in DNA collection, and to the clinical staff. They thank Anne Friedrich, as well, for investigation of possibilities for the modeling of TRPM1 on a three-dimensional basis. The project was financially supported by Agence Nationale de la Recherche (to S.S.B), Foundation Voir et Entendre and BQR (Bonus Qualité Recherche), Université Pierre et Marie Curie6 (to C.Z.), Foundation Fighting Blindness (FFB) (to I.A., grant no. CD-CL-0808-0466-CHNO; and the CIC503 recognized as an FFB center, grant no. C-CMM-0907-0428-INSERM04), EU FP7, Integrated Project “EVI-GENORET” (LSHG-CT-2005-512036), the Swiss National Science Foundation (to F.L.M. and D.F.S., grant no. 320030_127558), Research Foundation Flanders (FWO) (to B.P.L., grant no. G.0043.06N), and the Deutsche Forschungsgemeinschaft (to S.K., B.W., and E.Z.; grant no. KFO134-KO2176/2-1 and KFO134-ZR1/17-2). Download .pdf (.02 MB) Help with pdf files Document S1. One Table The URLs for data presented herein are as follows:ESEfinder, http://rulai.csh2.edu/tools/ESEGenCards, PolyPhen (Polymorphism Phenotyping), http://tux.embl-heidelberg.de/ramensky/National Center for Biotechnology Information (NCBI), http://ncbi.nlm.nih.gov/Online Mendelian Inheritance in Man http (OMIM), http://ncbi.nlm.nih.gov//Omim/SIFT (Sorting Intolerant From Tolerant), http://blocks.fhcrc.org/sift/SIFT.htmlUniversity of California-Santa Cruz (UCSC) Human Genome Browser http://genome.ucsc.edu/UniProtKB-Swiss-Prot, http://www.uniprot.org Recessive Mutations of the Gene TRPM1 Abrogate ON Bipolar Cell Function and Cause Complete Congenital Stationary Night Blindness in HumansLi et al.The American Journal of Human GeneticsOctober 29, 2009In BriefComplete congenital stationary night blindness (cCSNB) is associated with loss of function of rod and cone ON bipolar cells in the mammalian retina. In humans, mutations in NYX and GRM6 have been shown to cause the condition. Through the analysis of a consanguineous family and screening of nine additional pedigrees, we have identified three families with recessive mutations in the gene TRPM1 encoding transient receptor potential cation channel, subfamily M, member 1, also known as melastatin. A number of other variants of unknown significance were found. Full-Text PDF Open ArchiveMutations in TRPM1 Are a Common Cause of Complete Congenital Stationary Night Blindnessvan Genderen et al.The American Journal of Human GeneticsNovember 9, 2009In BriefCongenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impaired night vision and variable decreased visual acuity. We report here that six out of eight female probands with autosomal-recessive complete CSNB (cCSNB) had mutations in TRPM1, a retinal transient receptor potential (TRP) cation channel gene. These data suggest that TRMP1 mutations are a major cause of autosomal-recessive CSNB in individuals of European ancestry. Full-Text PDF Open Archive" @default.
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