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Identification of the Gene and the Mutation Responsible for the Mouse nob Phenotype

¹From the Departments of Biochemistry and Molecular Biology, ²Ophthalmology and Visual Sciences, and ⁸Psychological and Brain Sciences, University of Louisville, Louisville, Kentucky; ³Research Service, Cleveland VA Medical Center, Cleveland, Ohio; ⁴Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio; the ⁵Departments of Psychology and ⁹Neurosciences, Case Western Reserve University, Cleveland, Ohio; the ⁶Research Service, Atlanta VA Medical Center, Decatur, Georgia; and the ⁷Department of Ophthalmology, Emory University, Atlanta, Georgia.

	Abstract

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PURPOSE. The available evidence indicates that the naturally occurring mouse mutant nob (no b-wave) provides an animal model for the complete form of human X-linked congenital stationary night blindness (CSNB1). The goals of the present study were to identify the nob gene defect, to characterize the expression pattern of the involved gene, and to assess visual sensitivity in nob mice.

METHODS. Positional cloning, screening of candidate genes, and sequencing were used to identify the nob gene. The expression pattern of the nyx gene was examined with Northern blot analysis and in situ hybridization. Visual sensitivity was measured with an active avoidance behavioral test.

RESULTS. The nob phenotype is caused by an 85-bp deletion in the mouse nyx gene, which encodes the nyctalopin protein. Expression of nyx was most abundant in the retina and, in particular, in the inner nuclear layer. The nyctalopin protein contains 11 leucine-rich repeats and is flanked by cysteine rich regions, which identifies it as a member of the small leucine rich proteoglycan family. Behavioral testing shows that nob mice have a significant decrease in visual sensitivity.

CONCLUSIONS. The nob mouse is a model for human CSNB1. This model will be useful in defining the role of nyctalopin in signal transmission between photoreceptors and retinal bipolar cells.

Defects in the DBC signal transduction cascade are reflected as abnormalities in the electroretinogram (ERG) b-wave, which is generated by DBC activity.^{2 3} For example, in mice without either the mGluR6 receptor⁴ or the -subunit of G_o,⁵ the ERG b-wave is absent, although photoreceptor function, reflected in the a-wave,⁶ is normal, as is overall retinal morphology. We have identified a spontaneous mouse mutant (nob; no b-wave) in which the ERG⁷ is similar to that recorded in mGluR6 and G_o-null mice. The ERG a-wave of nob mice is normal, indicating that rod phototransduction is unaffected by the mutation. The absence of a b-wave in nob mice indicates that the photoreceptors fail to activate DBCs.^{7 8} Similar to retinas of mGluR6- and G_o-null mice,^{5 9} those of nob mice appear morphologically normal at the light and electron microscopic levels.^{7 8}

From these findings, coupled with our observation that nob is an X-linked trait, we have suggested that the nob mouse may be a model for the complete form of human X-linked congenital stationary night blindness (CSNB1).^{7 8 10} Among other clinical features, patients with CSNB1 have an essentially complete loss of the ERG b-wave and a profound loss of rod-mediated visual sensitivity,¹¹ traits that are consistent with a failure of synaptic transmission between photoreceptors and DBCs. CSNB1 is caused by mutations in the nyx gene, which encodes a novel leucine-rich repeat (LRR) protein of unknown function called nyctalopin.^{12 13}

In the present study, linkage mapping refines the location of the nob gene, and subsequent sequence analysis shows that the mutant phenotype is caused by an 85-bp deletion in the nyx gene. Expression of nyx is most abundant in cells within the inner nuclear layer (INL) of the retina, and behavioral studies demonstrate that nob mice have a marked loss of visual sensitivity. Taken together, these results confirm the initial suggestion that the nob mouse is a model for human CSNB1.⁷ As such, this mouse mutant has direct relevance to understanding CSNB1 and could be used to develop experimental treatments for this disorder. In addition, these results indicate that nyctalopin plays an important role in the photoreceptor to the DBC signal transduction process and the availability of this mouse model will help us to a better understanding of this process.

	Material and Methods

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Genetic Mapping
All procedures performed in animals were approved by the local institutional animal care and use committee and conformed to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Intra- and interspecific breeding strategies were used to generate mouse pedigrees for linkage analyses. With the exception of nob mice, all other mouse strains were obtained from The Jackson Laboratory (Bar Harbor, ME). Affected BALB/cByJ nob males were crossed to normal C57BL/6J females. The F1 female offspring, who must be carriers for the nob mutation (nob/+), were backcrossed to BALB/cByJ nob males. A total of 469 mice from these intraspecific backcrossed mice were used in the linkage analysis. To increase the number of polymorphic markers that were informative for linkage analyses, we also used an interspecific cross in which BALB/cByJ nob/nob (Mus musculus) females were mated to SPRET/Ei (Mus spretus) males. The F1 female carriers (nob/+) were backcrossed to affected BALB/cByJ males, yielding 303 interspecific backcrossed mice. All mice were phenotyped at 4 to 5 weeks of age, by using ERG, and were genotyped with various markers used for linkage analysis, as described previously.^{7 10}

Isolation of New Markers Near the nob Critical Region
Several informative markers (DXMit103, DXMit187, DXMit52, DXMit85, DXMit139, and DXMit72) were present in the nob critical region, and each was used to isolate bacterial artificial chromosome (BAC) clones, by using a PCR-based strategy from commercial libraries (Research Genetics, Huntsville, AL, or Incyte Genomics, Palo Alto, CA). BAC contigs were extended by end-sequencing and rescreening the libraries until a BAC contig covering most of the nob critical region was assembled (Gregg R, unpublished results, 2002). Sequence from fragments of the BAC clones were used to identify additional polymorphic markers in the nob critical region. One marker, UL107, was identified from BAC 402g19 (Research Genetics). Primer sequences to amplify this marker are UL107f (5'-cccgtccctcaaacaaataa-3') and UL107r (5'-gccagatatgaccccagaga-3'). PCR conditions were as described previously.¹⁰

Isolation of the Murine nyx Gene
To isolate the murine nyx gene, a cDNA clone (GenBank accession no. AI861796; http://www.ncbi.nlm.nih.gov/Genbank/; GenBank is provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD), containing a fragment of cDNA from the human NYX gene was obtained from the Image consortium (http://www.info@image.llnl.gov/; provided in the public domain and hosted by The Lawrence Livermore National Laboratory, Livermore, CA). The cDNA insert was isolated, radiolabeled by the random-primed oligo-labeling method (Amersham Pharmacia Biotech, Piscataway, NJ), and hybridized to BAC clones encompassing the nob critical region. For two positively hybridizing BACs, EcoRI and HindIII shotgun libraries were constructed and screened. A clone containing a 5.9-kb EcoRI fragment was identified from two different BACs and found through sequencing to contain exon 3 of the nyx gene. The remainder of the murine nyx gene was isolated by cloning and sequencing fragments that overlapped this clone. DNA fragments were sequenced using fluorescent cycle sequencing and analyzed on a DNA sequencer (model CEQ2000XL; Beckman-Coulter, Fullerton, CA). The sequence of the murine nyx gene was obtained by a combination of end sequencing of EcoRI and HindIII subclones of one BAC clone (402g19), primer walking, and import of sequences from the Ensembl trace database (http://www.ensembl.org/; provided in the public domain by the European Molecular Biology Lab [EMBL], Heidelberg, Germany, and the Sanger Centre, Hinxton, UK).¹⁴ The predicted coding region was determined from expressed sequence tag EST and genomic sequence. The several Internet-accessible resources that were used to analyze the nyx protein sequence will be indicated later.

In Situ Hybridization
After mice were killed with CO₂, their eyes were enucleated and the eyecup isolated and immersion fixed for 20 minutes in 4% paraformaldehyde (Sigma Chemical Co., St. Louis, MO) in 0.1 M sodium phosphate buffer (Na-PB; pH 7.4). The retina was then removed from the eyecup, cryoprotected in a graded series of sucrose solutions in Na-PB, embedded, and frozen in solution containing a 2:1 ratio of 20% sucrose to OCT (Tissue-Tek; Ted Pella, Inc., Redding, CA). Transverse sections (12 µm) of the retina were cut on a cryostat and mounted on microscope slides. A 491-bp fragment of the mouse nyx cDNA and a 1.5-kb fragment of the murine rhodopsin cDNA were cloned into two respective vectors (pCRII-TOPO; Invitrogen Inc., Carlsbad, CA; and pBluescript SK, Stratagene, Inc., La Jolla, CA). Plasmid DNA was purified on a CsCl gradient, linearized using appropriate enzymes, and antisense and sense digoxigenin-labeled (Roche Diagnostics, Mannheim, Germany) cRNAs were synthesized with SP6 and T7 polymerases and an in vitro transcription kit (Maxiscript; Ambion, Inc., Austin, TX). The labeled cRNA probes were quantified by agarose gel electrophoresis and dot blot analysis. In situ hybridization reactions were performed as described.¹⁵

Behavioral Analyses
Light sensitivity was evaluated in a two-way active-avoidance paradigm, using a shuttle box as described previously.¹⁶ Each training and testing period consisted of 100 trials, which began with a 3-minute acclimation period. In each trial, a light stimulus on one side of the box preceded the presentation of a mild foot shock (0.8 mA) on the same side by 10 seconds. The duration (20–35 seconds) of the foot shock was randomized, which also resulted in randomization of the interflash interval. Animals could either avoid or escape the shock at any point during each trial by moving to the dark or "safe" side of the cage. Each animal was trained for eight consecutive days with an unattenuated light stimulus. After the task had been learned, neutral density filters (Oriel, Stratford, CT) were used to reduce the intensity of the light cue.

	Results

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Genetic Localization
Our genetic mapping results and the localization of the nob (nyx) gene on the mouse X chromosome are summarized in Figure 1A . Previously, we located the nob gene between DXMit54 at 3.8 centimorgans (cM) and Ube1x at 5.7 cM on the mouse X chromosome.¹⁰ This interval included several DXMit markers (DXMit103, -187, -52, -85, -139, and -72¹⁷ ) that were informative in our interspecific backcross pedigree (Fig. 1A) . The presence of recombinants in the interspecific pedigree with DXMit54 and DXMit139 restricted the nob critical region between these markers, which represents a 0.9-cM region. None of these markers were informative in the intraspecific pedigree. In addition, a newly identified marker, UL107, was generated within the critical region from a BAC 402g19 (Research Genetics) clone containing markers DXMit85 and was informative for most of the intraspecific and all the interspecific pedigrees. UL107 showed no recombination with the nob phenotype in a total of 772 informative meioses, indicating that the mutant gene was close to this marker. Subsequent work placed UL107 only 18.4-kb telomeric to the nyx gene.

View larger version (65K): [in this window] [in a new window]   FIGURE 1. Map of nob critical region and the nyctalopin sequence. (A) The nob critical region was defined previously.10 Numbers indicate distance in centimorgans. The refined critical region based on recombinant chromosomes in two pedigrees is shown expanded on the second line. The number of recombinants with each marker in each of the two pedigrees is indicated below the map. (B) Comparison of the mouse (M) and human (H, GenBank accession no. AF254868) proteins. The signal sequence and the LRRs are shown by horizontal lines above the sequence. The predicted cleavage site (GGA) for attaching the putative GPI anchor site in human is underscored. Identical amino acids are shown in black, conservative substitutions in red, and nonconservative substitutions in purple. Inverted triangle: position at which the normal amino acid sequence is truncated in the nob mouse.

As does the human gene, nyx contains three exons, with exons 2 and 3 encoding the open reading frame (ORF). The encoded mouse protein, nyctalopin, is 476 amino acids with a predicted molecular weight of 52,429. Figure 1B shows a comparison between the amino acid sequences of the mouse (top line) and human (bottom line) proteins. Exact matches are shown in black, conservative substitutions are shown in red, and nonconservative substitutions are shown in purple. Murine nyctalopin contains a signal sequence¹⁸ and 11 LRRs, predicted by the Simple Modular Architecture Research Tool (SMART) program¹⁸ (smart.embl-heidelberg.de/; provided in the public domain by EMBL). These are flanked by regions rich in cysteine and are referred to as LRRNT and LRRCT (red and green lines, respectively; Pfam database, http://pfam.wustl.edu/; provided in the public domain by Washington University, St. Louis, MO). There are several serine and threonine residues in the carboxyl terminus (Fig. 1B , underlined) that show potential for O-glycosylation (http://www.cbs.dtu.dk/services/NetOGlyc/; provided in the public domain by the Center for Biological Sequence Analysis, The Technical University of Denmark, Lyngby, Denmark). The overall amino acid sequences of the mouse and human nyctalopin are 83% identical and 86% similar in terms of their protein structure. Considering just the core LRR portion of the mouse protein (mouse amino acids 23–366), it is 91% identical with human. The most disparate regions between the two species are the amino- and carboxyl-terminal ends. In humans, there are two possible initiation codons near the amino terminus and the codon that maximized the length of the ORF was chosen.^{12 13} In mouse, the first of these two initiation codons is absent, indicating that the mouse protein is either five amino acids shorter at the amino-terminal end than in humans, or that the second initiation codon is used in humans, which is the most likely explanation given the otherwise high degree of similarity between the human and mouse genes. However, it should be noted that the translation start prediction program NetStart (http://www.cbs.dtu.dk/services/NetStart/; provided by The Technical University of Denmark) gives significant prediction scores for both the ATG that maximizes the human ORF (starting at base pair 99 in GenBank accession no. AF254868), as well as the ATG that encodes methionine-6. Confirmation of the correct start site in human necessitates end sequencing of nyctalopin.

Murine nyctalopin, as well as the human orthologue, is predicted to have 9 typical LRRs that are flanked by LLRs rich in cysteines (LRRNT and LRRCT). These repeats are present in a large number of other proteins and are involved in protein–protein interactions.¹⁸ The flanking cysteine-rich repeats make the mouse protein a member of the small-leucine–rich proteoglycans (SLRPs).¹⁹ Mouse nyctalopin includes an amino terminal signal sequence and a carboxyl-terminal region that may be cleaved. There is little support for a predicted GPI anchor sequence in the mouse (EXPASY, DPGI program, http://us.expasy.org/; provided in the public domain by the Swiss Institute of Bioinformatics, Geneva, Switzerland), which was predicted for the human protein.^{12 13} This difference is not caused by sequence errors in the mouse, because these regions generated by sequencing two independent mouse BAC clones from 129Sv libraries match exactly those generated by the mouse genome sequencing project. The localization of two transmembrane domains to the carboxyl-terminal region also have some support from the results using several analysis programs (TMHMM, TopPred2 via the ProteinPredict server, http://www.embl-heidelberg.de/predictprotein.html/; provided in the public domain by EMBL).²⁰ These data indicate that most of the murine nyctalopin protein is extracellularly anchored to the cell surface by either one or two transmembrane domains. However, resolution of these differences between murine and human proteins necessitates direct experimental confirmation.

Expression of nyx
To examine the expression pattern of nyx, we used Northern blot analysis and in situ hybridization. Figure 2A shows a Northern blot that indicates that the nyx gene is expressed abundantly in normal retina and at a lower level in retina of nob mice. The nyctalopin transcript is undetectable in normal brain and kidney. From these data, we estimate that the nyx mRNA is 7 kb in length. Shown for comparison, is the same blot stripped and rehybridized with a probe for ß-actin, demonstrating equivalent RNA loading across lanes (Fig. 2B) . The size of mouse nyx mRNA is considerably larger than the cDNA sequence reported for human NYX,^{12 13} although neither group predicted transcript size on the basis of Northern blot analysis. This larger size may result from 5' and/or 3' untranslated regions, which were not represented in the human cDNA sequences. Analyses of mouse genomic DNA sequence downstream of the termination codon indicate that there are three possible polyadenylation sites (polyadq form, http://argon.cshl.org/tabaska/polyadq_form.html; provided in the public domain by Cold Spring Harbor Laboratory, Cold Spring Harbor, NY), which also are associated with ESTs. Use of one or more of these sites would produce transcripts of a length more consistent with our Northern blot data. These data also indicate that nyx is expressed at lower levels in nob mouse retina (Fig. 2A , compare lanes 1 and 2). This presumably results from instability of the mRNA containing the 85-bp deletion in exon 3 (see below).

View larger version (74K): [in this window] [in a new window]   FIGURE 2. Expression of mouse nyx. (A) Northern blot analyses of expression of nyx in retina, brain, and kidney from control mice and retina from nob mice. (B) Blot shown in (A), stripped and reprobed with a ß-actin probe to demonstrate that approximately the same amount of RNA was loaded for each sample. (C) In situ hybridization. Left: staining after hybridization with an antisense probe to rhodopsin (color reacted for 1 hour). Middle and left: staining after hybridization to antisense and sense nyx probes, respectively (reacted for 12 hours). These data show that nyx is expressed most abundantly in the INL.

Mutation Responsible for the nob Phenotype
To determine whether a mutation in the nyx gene was present in the nob mice, we designed mouse-specific primers and used PCR to amplify fragments encompassing each exon of the nyx gene from both nob and control retinal cDNAs. One PCR product, which encompassed most of exon 3, was significantly shorter when DNAs from nob mice were used as template. The short fragment cosegregated with the nob phenotype, whereas the long fragment segregated with the normal phenotype, and obligate carrier females had both fragments (Figs. 3A 3B) . When both PCR products were cloned and sequenced, an 85-bp deletion in exon 3 was found in the fragment amplified from the nob mice (Fig. 3C) . The deletion results in a frame-shift mutation that fuses 170 amino acids that do not match nyctalopin, to 188 amino acids from the amino terminus of the normal nyctalopin protein. This results in a loss of 288 amino acids from the carboxyl terminus of the protein, which includes seven LRRs. These data, combined with the decrease in mRNA expression observed in nob retina (Fig. 2A) , indicate that this mutation is most likely a loss-of-function mutation.

View larger version (49K): [in this window] [in a new window]   FIGURE 3. The nob mice have an 85-bp deletion in the nyx gene. (A) Pedigree showing the inheritance pattern of the nob phenotype. (B) Image of an ethidium bromide–stained agarose gel showing the fragments obtained using primers that flank the deletion present on the nob allele. Band 1 (normal, allele 1) is present in normal males and obligate carrier females. Band 2 (allele 2, the smaller fragment) is present in all carrier females and affected males, arising from the deleted nyx gene in these mice. (C) Sequence traces obtained from cloned fragments from normal and nob mice illustrating the deletion. The exact deletion points are not known because there is a 4-base direct repeat (GCAT) that is present at both the 5' and 3' deletion breakpoints.

View larger version (22K): [in this window] [in a new window]   FIGURE 4. Visual sensitivity is reduced in nob mice. Left: acquisition of an active avoidance task using a light cue by control mice (n = 7), nob mice (n = 7), and mice with eyes enucleated (n = 2). Right: performance of control and nob mice as the intensity of the light cue was reduced by 2, 3, or 4 log units, by addition of neutral density filters. Data points indicate the mean ± SE.

	Discussion

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The physiological phenotype of the nob mutant is characterized by a reduction in the ERG b-wave and a marked decrease in light sensitivity, although the gross morphology of the retina is normal. Taken together, these features indicate that there is a failure in synaptic transmission between photoreceptors and DBCs in these mice. Our in situ hybridization data suggest that nyx is expressed primarily in cells in the retinal INL. This localization lends support to the hypothesis that the defect in nob mice and patients with CSNB1 is localized postsynaptically. However, when the human NYX gene was used to probe paraffin-embedded human retina, all retinal cell bodies were labeled.¹² This difference in expression patterns could reflect either a species difference or the unusually long incubation times (3–5 days) needed to obtain labeling with the paraffin-embedded human retinal sections. Lending further support to a postsynaptic location for the defect is evidence that the kinetics and amplitude of the a-wave of the ERG is normal in both nob mice and patients with CSNB1, reflecting a normal response of their photoreceptors to a light stimulus. That said, it is possible that there is a defect in neurotransmitter release. However, our observations of defects in outer plexiform layer (OPL) synaptic structure in mice without the L-type calcium channel in photoreceptors argues otherwise.¹⁶ These mice without the ß₂- subunit of voltage-dependent calcium channels in the central nervous system and are called CNS-ß₂-null mice. Because this subunit is necessary for channel assembly, the _1F subunit is absent from the OPL, and presumably there is no neurotransmitter release, which is consistent with the absence of a b-wave in the ERG from these mice. The CNS-ß₂ null mice also have a greatly thinned OPL and have abnormal ribbon synapses. We have interpreted these data to indicate that release of neurotransmitter is essential for synaptic formation and/or development. Therefore if neurotransmitter were not released from the terminals of the rod photoreceptors in the nob mice, we might expect a similar abnormality in the OPL, which is clearly not the case.

Our previous ERG data, combined with our new behavioral assays of light sensitivity firmly establish that the nob phenotype is identical with the CSNB1 phenotype in humans. It is notable that nob mice and patients with CSNB1 do not completely lose visual function. The nob mice can learn a visual task if the light stimulus is bright, and evoked potentials recorded over their visual cortex are present at stimulus offset.⁷ Patients with CSNB1 retain reasonably good visual acuity, light sensitivity and color vision under daylight conditions.¹¹ Moreover, analysis of the cone ERG of patients with CSNB1 indicates that response components generated to flash offset are normal.^{21 22} These observations suggest that the function of DBCs may be selectively compromised in both the rod and cone pathways in nob retinas and that the residual visual function present in nob mice and patients with CSNB1 is mediated through the HBC pathway.

Signaling through rod DBCs requires that glutamate is released by photoreceptors and binds to the mGluR6 receptor that is located on the rod bipolar cell dendrite.²³ The mGluR6 receptor is G-protein–coupled, and its activation initiates an intracellular cascade that terminates in closure of a cation channel.²⁴ Both the specific steps in this cascade and the identity of the cation channel are presently unknown, although recently one important component, G_o has been identified.⁵ Given our data, it is likely that nyctalopin is either directly involved in the DBC signal-transduction pathway or in the organization of the protein complexes of this pathway. Future characterization of nyctalopin and the nob mouse will be instrumental in elucidating the role of this protein in the signaling processes of retinal DBCs and in examining potential treatments for patients with CSNB1.

	Footnotes

 
Supported by National Eye Institute Grants R01 EY12354 (RGG, MAM, NSP), National Science Foundation (NSF) Cooperative Agreement OSR-9452895 (RGG, MAM), the University of Louisville Center for Genetics and Molecular Medicine (RGG), and the Department of Veterans Affairs (NSP, SLB, MTP).

Submitted for publication May 28, 2002; revised August 6, 2002; accepted August 14, 2002.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 1734 solely to indicate this fact.

Corresponding author: Ronald G. Gregg, Department of Biochemistry and Molecular Biology, University of Louisville, 319 Abraham Flexner Way, Louisville, KY 40202; ron.gregg{at}louisville.edu.

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