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X-Linked Congenital Stationary Night Blindness

Synonym: X-Linked CSNB. Includes: CACNA1F-Related X-Linked Congenital Stationary Night Blindness (CSNB2A), NYX-Related X-Linked Congenital Stationary Night Blindness (CSNB1A)

, PhD, MD, , PhD, and , MD, CM.

Author Information
, PhD, MD
Clinical Geneticist, Department of Genetics
Children's Hospital of Eastern Ontario
Associate Professor, Department of Pediatrics
University of Ottawa
Ottawa, Ontario, Canada
, PhD
Departments of Ophthalmology and Physiology
University of Alberta
Edmonton, Alberta, Canada
, MD, CM
Departments of Ophthalmology and Medical Genetics
University of Alberta
Edmonton, Alberta, Canada

Initial Posting: ; Last Update: April 26, 2012.

Summary

Disease characteristics. X-linked congenital stationary night blindness (CSNB) is characterized by: non-progressive retinal findings of reduced visual acuity ranging from 20/30 to 20/200; defective dark adaptation; refractive error, most typically myopia ranging from low (-0.25 diopters [D] to -4.75 D) to high (≥-10.00 D) but occasionally hyperopia; nystagmus; strabismus; normal color vision; and normal fundus examination. Two overlapping, yet distinct, phenotypes are recognized:

  • Complete CSNB (CSNB1A), caused by mutations in NYX (45%)
  • Incomplete CSNB (CSNB2A), caused by mutations in CACNA1F (55%)

Diagnosis/testing. Diagnosis is based on clinical findings, characteristic findings on electroretinography (ERG), family history, and molecular genetic testing of NYX and CACNA1F, the only two genes in which mutations are known to cause X-linked CSNB.

Management. Treatment of manifestations: Glasses or contact lenses to treat refractive error (myopia or hyperopia); conventional strabismus surgery may be required to improve binocularity or head posture.

Prevention of secondary complications: On occasion, strabismus surgery to improve functional range of null point.

Surveillance: At a young age yearly eye examinations with refraction to identify and treat myopia as early as possible.

Agents/circumstances to avoid: Reduced visual acuity and difficulties seeing at night may preclude driving a car or restrict the class of driving license.

Genetic counseling. X-linked CSNB is inherited in an X-linked manner. The father of an affected male will not have X-linked CSNB nor will he be a carrier of the disease-causing mutation. If the mother of the proband is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected. Males with X-linked CSNB will pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for families in which the disease-causing mutation has been identified.

Diagnosis

Clinical Diagnosis

Affected Males

A clinical diagnosis of X-linked congenital stationary night blindness (X-linked CSNB) can be made in a male with the following findings:

  • Reduced visual acuity. Vision is reduced in all affected males in the range of 20/30 (6/9; log MAR 0.1) to 20/200 (6/60; log MAR 1.0).
  • History of defective dark adaptation. Night blindness is a subjective finding; see Characteristic findings on ERG (electroretinography) for explanation of CSNB types 1 and 2.
    • Individuals with CSNB1A (complete X-linked CSNB caused by mutation of NYX) generally report severe night blindness.
    • Individuals with CSNB2A (incomplete X-linked CSNB caused by mutation of CACNA1F) do not uniformly report severe night blindness.
  • Myopia. Myopia may range from low (-0.25 diopters [D] to -4.75 D) to high (≥ -10.00 D) [Boycott et al 2000, Allen et al 2003]. A few affected individuals have hyperopia.
  • Nystagmus and strabismus
    • 50%-70% of affected individuals have nystagmus and strabismus [Boycott et al 2000, Allen et al 2003].
    • Transient head posture with nystagmus was noted in the first two years of life in eight individuals with X-linked CSNB secondary to mutations in CACNA1F and one with a mutation in NYX [Simonsz et al 2009].
    • In a large Mennonite cohort with incomplete X-linked CSNB, at least one of the following was not present in 72% of cases: myopia, nystagmus, or night blindness [Boycott et al 2000].
  • Normal color vision. However, individuals with a severe X-linked CSNB may show mild color vision deficits.
  • Normal fundus examination. However, persons with high myopia may show myopic degeneration.
  • Family history consistent with X-linked inheritance
  • Characteristic findings on ERG
    • ERG is used to assess the changes in electrical activity of the retina in response to light. The b-wave is caused by the depolarization of ON bipolar cells in response to light stimuli and is strictly dependent on synaptic transmission from photoreceptors to ON bipolar cells.
    • Individuals with X-linked CSNB have reduced scotopic b-wave amplitudes in response to bright flashes after dark adaptation (Figure 1). The resulting ERG waveform is essentially a negative wave (amplitude of the a-wave is larger than that of the b-wave) [Miyake et al 1986], referred to as the Schubert-Bornschein form [Schubert & Bornschein 1952].
    • Based primarily on the results of the scotopic ERG, X-linked CSNB may be further differentiated as follows:
      • Complete X-linked CSNB (CSNB1A): b-wave is severely reduced or not measurable (i.e., absent).
      • Incomplete X-linked CSNB (CSNB2A): b-wave is reduced but measurable.
    • The ERG can define specific retinal dysfunctions and, in general, differentiate the forms of X-linked CSNB (Table 1) to identify the gene most likely to be involved (see Testing Strategy).
Figure 1

Figure

Figure 1. Representative full-field ERGs recorded from three males:
A. Unaffected 35-year-old
B. 66-year-old with CSNB1A (mutation in NYX)
C. 35-year-old with CSNB2A (mutation in CACNA1F)
Arrows indicate the b-wave, (more...)

Table 1. ERG Findings in Complete and Incomplete X-Linked CSNB

ERG FindingComplete (CSNB1A)Incomplete (CSNB2A)
Scotopic rod b-waveSeverely reduced or absentReduced
Mixed scotopic a-waveNormalSlightly reduced
Mixed scotopic b-waveReducedReduced
Scotopic OPAbsentSlightly reduced
Photopic a-waveNormal, slightly reduced, saw-tooth (square) shapedReduced
Photopic b-waveSlightly reducedReduced
Photopic OPLost, except for OP4All are lost
30-Hz flickerNormal/slightly reducedReduced with double peak

OP = oscillatory potential

Note: Pupillary responses have been described as "paradoxical" in the literature and textbooks (i.e., miosis of pupils when lights are turned off, as opposed to dilation). This description predates genotyping. In 17 individuals with incomplete X-linked CSNB ages five to 51 years examined by one of the authors, none clearly demonstrated a paradoxical papillary response. Further clarification of the presence or absence of this phenomenon in individuals with X-linked CSNB may require measurement with pupillometry.

Carrier Females

In general, carrier females do not exhibit clinical signs of X-linked CSNB; however, on occasion there have been reports of females who are homozygous for mutations in CACNA1F with signs similar to those in males [Bech-Hansen et al 1998].

ERG changes that may be observed in obligate carriers of X-linked CSNB:

Molecular Genetic Testing

Genes. NYX and CACNA1F are the two genes in which mutations are known to cause X-linked CSNB. (See Table A for chromosomal locus and protein name for these genes.)

Table 2. Summary of Molecular Genetic Testing Used in X-Linked Congenital Stationary Night Blindness

Gene 1 / CSNB PhenotypeProportion of X-Linked CSNB Attributed to Mutations in This Gene 2Test MethodMutations Detected 3
NYX / CSNB1A 445%Sequence analysisSequence variants 5,6,7
Deletion / duplication analysis 8Exonic and whole-gene deletions 79
CACNA1F / CSNB2A 1055%Targeted mutation analysisc.3167_3168dupC 11
Sequence analysisSequence variants 5,6,7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. Zeitz [2007]

3. See Molecular Genetics for information on allelic variants.

4. Bech-Hansen et al [2000], Pusch et al [2000]

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

7. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. Pusch et al [2000]

10. Bech-Hansen et al [1998], Strom et al [1998]

11. Present in the Dutch-German Mennonite population [Bech-Hansen et al 1998, Boycott et al 2000].

Testing Strategy

To establish the diagnosis in a proband. A male with reduced visual acuity, myopia, nystagmus, strabismus, and normal color vision may be suspected of having X-linked CSNB. In general, the diagnosis of X-linked CSNB can be made by ophthalmologic examination (including electroretinography) and family history consistent with X-linked inheritance.

To confirm the diagnosis in a proband using molecular genetic testing (see Table 1)

  • Alternative 1. Sequential molecular genetic testing. For individuals with a clear family history consistent with X-linked inheritance, electroretinographic findings can be used to differentiate between CSNB1A and CSNB2A and can direct molecular genetic testing to the appropriate gene.

    Note: For individuals of Dutch-German Mennonite descent and features of CSNB2A, targeted mutation analysis of the founder mutation in CACNA1F can be performed.
  • Alternative 2. Multi-gene testing. For individuals without a clear family history consistent with X-linked inheritance, consider using a multi-gene congenital stationary night blindness panel that includes NYX and CACNA1F as well as additional genes associated with CSNB (see Differential Diagnosis).

    Note: These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation(s) in any given individual with the CSNB phenotype also varies.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this X-linked disorder and may develop some related findings.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

X-linked congenital stationary night blindness (CSNB) is a congenital non-progressive retinal disorder characterized by defective night vision, reduced visual acuity, myopia, nystagmus, and strabismus (see Clinical Diagnosis).

Genotype-Phenotype Correlations

CSNB1A, the complete form of X-linked CSNB, is caused by mutations in NYX [Bech-Hansen et al 2000, Pusch et al 2000].

CSNB2A, the incomplete form of X-linked CSNB, is caused by mutations in CACNA1F [Bech-Hansen et al 1998, Strom et al 1998].

Penetrance

Penetrance of CSNB1A and CSNB2A is probably 100%, but expressivity is variable [Boycott et al 2000]; clinically mild cases may be missed if electroretinography is not performed.

Nomenclature

X-linked CSNB has in the past been referred to as Schubert-Bornschein CSNB, which is a reference to the characteristic "negative" waveform (a-wave larger than the b-wave) of the ERG seen in both X-linked forms of CSNB [Schubert & Bornschein 1952].

The terms CSNB1 and CSNB2 are sometimes used as abbreviations for complete and incomplete CSNB irrespective of the mode of inheritance; originally the terms referred to the two X-linked entities of CSNB.

Prevalence

The prevalence of X-linked CSNB is not known.

A founder effect has been reported in individuals with CSNB2A who are of Dutch-German Mennonite descent [Bech-Hansen et al 1998, Boycott et al 1998, Boycott et al 2000]. A common mutation in NYX has been identified in Flemish individuals from Belgium with CSNB1A [Leroy et al 2009].

Differential Diagnosis

See Night Blindness, Congenital Stationary: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Normal Fundus

X-linked congenital stationary night blindness (X-linked CSNB) is characterized by a normal fundus. Only a few conditions may initially be confused with the X-linked form of CSNB:

CSNB (non X-linked). Family history consistent with X-linked inheritance may differentiate the X-linked forms of CSNB from the autosomal dominant and recessive forms (see OMIM Phenotypic Series).

Blue cone monochromacy, inherited in an X-linked manner, is characterized by poor vision and nystagmus. This condition differs clinically from X-linked CSNB in the following ways:

  • Color vision testing is abnormal.
  • ERG reveals almost completely abolished photopic ERG contrasting with normal or minimally affected scotopic ERG.
  • Whereas fundus examination in young males is normal, some males develop macular atrophy in late adulthood.

Blue cone monochromacy results from alterations in the locus control region of the red and green pigment genes. (See Red-Green Color Vision Defects.)

X-linked motor nystagmus can be distinguished from X-linked CSNB by the finding of normal ERG. Mutations in FRMD7 are causative [Tarpey et al 2006].

Abnormal Fundus

A few conditions with an abnormal fundus examination and an X-linked pattern of inheritance could be confused with X-linked CSNB.

  • X-linked ocular albinism. Clinical features of iris transillumination and foveal hypoplasia are present in X-linked ocular albinism and not in CSNB. The ERG in X-linked ocular albinism does not show the selective reduction in the amplitude of the b-wave observed in X-linked CSNB. In X-linked ocular albinism the visual evoked potential (VEP) responses show a propensity for more crossing fibers than expected at the level of the chiasm. Mutations in OA1 are causative.
  • X-linked juvenile retinoschisis. Visual acuity in X-linked juvenile retinoschisis is reduced to the same range seen in X-linked CSNB. Fundus examination shows foveal schisis or foveal findings in virtually all affected males and approximately 50% have areas of peripheral retinoschisis, neither of which finding is seen in X-linked CSNB. In X-linked juvenile retinoschisis the ERG shows a selective reduction in the amplitude of the b-wave. Mutations in RS1 are causative.

The following autosomal recessive conditions, also characterized by abnormal fundus, are included here as they are non-progressive and considered part of the spectrum of differential diagnoses of X-linked CSNB:

  • Oguchi disease is a form of CSNB reported in the Japanese that is caused by mutations in either SAG, the gene encoding arrestin, or GRK1, the gene encoding rhodopsin kinase. The fundus has an abnormal color, which becomes normal with prolonged dark adaptation (the Mizuo phenomenon) [Dryja 2000].
  • Fundus albipunctatus is a form of CSNB caused by mutations in RDH5, the gene encoding retinol dehydrogenase. The fundus shows discretely scattered white retinal dots. The ERG, when recorded under standard conditions, shows selective reduction in the b-wave, which normalizes with prolonged dark adaptation [Dryja 2000].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked congenital stationary night blindness (CSNB), the following evaluations are recommended:

  • Ophthalmologic examination
  • Electroretinography
  • Family history
  • Dark adaptation (optional)
  • Genetics consultation

Treatment of Manifestations

Coincident high myopia or hyperopia can be managed with glasses or contact lenses.

In some cases, conventional strabismus surgery may be required to improve binocularity or head posture.

Prevention of Secondary Complications

Occasionally, a boy with X-linked CSNB may adopt a cosmetically unacceptable or functionally awkward head posture to dampen the degree of nystagmus in a particular position of gaze (the so-called "null point"). In some instances the position of gaze for the null point may be shifted to a better functional range by carefully planned strabismus surgery.

Surveillance

Regular (yearly) eye examinations are recommended with refraction at a young age to monitor for the development of myopia.

Agents/Circumstances to Avoid

Reduced visual acuity and difficulties seeing at night may preclude driving a car or restrict the class of driving license.

Evaluation of Relatives at Risk

For infants identified with high myopia, unusual head posture or nystagmus and a family history of CSNB, ophthalmic examination and molecular genetic testing may confirm the diagnosis of CSNB, obviating the need for neuroimaging or clinical electrophysiologic testing under sedation or general anesthesia.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked congenital stationary night blindness (CSNB) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

  • The father of an affected male will not have X-linked CSNB nor will he be a carrier of the disease-causing mutation.
  • In a family with more than one affected male, the mother of an affected male is an obligate carrier.
  • Possible genetic explanations for a male proband with no family history of X-linked CSNB (i.e., a simplex case):
    • He has a de novo mutation and his mother is not a carrier.
    • His mother has a de novo mutation either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only). Germline mosaicism has not been reported in individuals with X-linked CSNB, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members. In both instances (a) and (b), other offspring of the proband's mother are at risk of inheriting the mutation; however, the sibs of the proband's mother are not at risk of having inherited the altered gene.
    • His mother has a mutation that she inherited from a maternal female ancestor.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has an altered allele, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected. In rare cases a female is affected, having inherited two mutant alleles, one from a carrier mother and one from an affected father.
  • If the altered allele cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Males with X-linked CSNB will pass the altered allele to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunts' offspring, depending on their gender, may be at risk of being carriers or of having X-linked CSNB.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the disease-causing mutation has been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and clarification of carrier status is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must be identified before prenatal testing can be performed. Usually fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like X-linked CSNB) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Foundation Fighting Blindness
    11435 Cronhill Drive
    Owings Mills MD 21117-2220
    Phone: 800-683-5555 (toll-free); 800-683-5551 (toll-free TDD); 410-568-0150
    Email: info@fightblindness.org
  • Foundation Fighting Blindness - Canada
    890 Yonge Street
    12th Floor
    Toronto Ontario M4W 3P4
    Canada
    Phone: 800-461-3331 (toll-free); 416-360-4200
    Fax: 416-360-0060
    Email: info@ffb.ca
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. X-Linked Congenital Stationary Night Blindness: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for X-Linked Congenital Stationary Night Blindness (View All in OMIM)

300071NIGHT BLINDNESS, CONGENITAL STATIONARY, TYPE 2A; CSNB2A
300110CALCIUM CHANNEL, VOLTAGE-DEPENDENT, ALPHA-1F SUBUNIT; CACNA1F
300278NYCTALOPIN; NYX
310500NIGHT BLINDNESS, CONGENITAL STATIONARY, TYPE 1A; CSNB1A

Molecular Genetic Pathogenesis

Genes associated with X-linked congenital stationary night blindness (X-linked CSNB) encode proteins that are specifically expressed in the retina: nyctalopin and voltage-dependent L-type calcium channel subunit alpha-1F (Cav1.4/α1F) for complete and incomplete CSNB, respectively. Mutations identified in these genes impinge on synaptic transmission from photoreceptors (rods and cones) to inner retinal cells.

NYX

Normal allelic variants. NYX spans approximately 28 kb of genomic DNA and comprises three exons.

Pathogenic allelic variants. The mutation spectrum is wide, including missense, nonsense, and splice site mutations, deletions, and insertions. More than 50% of the mutations documented have been missense [Zeitz et al 2005, Zeitz 2007]. A common mutation in a selected population has been reported (see Prevalence).

Normal gene product. NYX encodes nyctalopin, a protein of 481 amino acids in the small leucine-rich proteoglycan family. Nyctalopin contains a signal peptide, a set of 12 leucine-rich repeats, and a glycosylphosphatidylinositol (GPI)-anchoring sequence [Bech-Hansen et al 2000, Pusch et al 2000, Bech-Hansen et al 2005].

Abnormal gene product. Mutations in NYX are predicted to cause a number of functional defects in nyctalopin, including alterations in its conformation, loss of the GPI anchor, and deletions of a portion or all of the protein [Zeitz 2007].

CACNA1F

Normal allelic variants. CACNA1F spans approximately 28 kb of genomic DNA and comprises 48 exons.

Pathogenic allelic variants. See Table 3. The mutation spectrum is wide, including missense, nonsense, and splice site mutations, deletions, and insertions. More than 50% of the mutations identified have been nonsense [Zeitz et al 2005, Zeitz 2007]. A founder mutation in one population has been reported (see Prevalence).

Table 3. CACNA1F Pathogenic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequence
c.3167_3168dupC
(3166dupC)
p.Leu1056ProfsTer11
(Leu991insC)
NM_005183​.2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. CACNA1F encodes a protein in which one of the splice isoforms has 1966 amino acids (Cav1.4/α1F) and is a voltage-gated L-type calcium channel [Bech-Hansen et al 1998, Strom et al 1998].

Abnormal gene product. Expression studies have shown that some (not all) CACNA1F missense mutations alter the channel activation properties of the Cav1.4 calcium channel [McRory et al 2004, Hemara-Wahanui et al 2005, Hoda et al 2005]; other missense mutations may affect the assembly or expression of the presynaptic ribbon complex [Hoda et al 2006]. Nonsense and frameshift mutations are predicted to cause loss of channel function or/and photoreceptor synapses.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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  2. Bech-Hansen NT, Cockfield J, Liu D, Logan CC. Isolation and characterization of the leucine-rich proteoglycan nyctalopin gene (cNyx) from chick. Mamm Genome. 2005;16:815–24. [PubMed: 16261423]
  3. Bech-Hansen NT, Naylor MJ, Maybaum TA, Pearce WG, Koop B, Fishman GA, Mets M, Musarella MA, Boycott KM. 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;19:264–7. [PubMed: 9662400]
  4. Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B, Birch DG, Bergen AA, Prinsen CF, Polomeno RC, Gal A, Drack AV, Musarella MA, Jacobson SG, Young RS, Weleber RG. Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nat Genet. 2000;26:319–23. [PubMed: 11062471]
  5. Boycott KM, Pearce WG, Bech-Hansen NT. Clinical variability among patients with incomplete X-linked congenital stationary night blindness and a founder mutation in CACNA1F. Can J Ophthalmol. 2000;35:204–13. [PubMed: 10900517]
  6. Boycott KM, Pearce WG, Musarella MA, Weleber RG, Maybaum TA, Birch DG, Miyake Y, Young RS, Bech-Hansen NT. Evidence for genetic heterogeneity in X-linked congenital stationary night blindness. Am J Hum Genet. 1998;62:865–75. [PMC free article: PMC1377021] [PubMed: 9529339]
  7. Dryja TP. Molecular genetics of Oguchi disease, fundus albipunctatus, and other forms of stationary night blindness: LVII Edward Jackson Memorial Lecture. Am J Ophthalmol. 2000;130:547–63. [PubMed: 11078833]
  8. Hemara-Wahanui A, Berjukow S, Hope CI, Dearden PK, Wu SB, Wilson-Wheeler J, Sharp DM, Lundon-Treweek P, Clover GM, Hoda JC, Striessnig J, Marksteiner R, Hering S, Maw MA. A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation. Proc Natl Acad Sci U S A. 2005;102:7553–8. [PMC free article: PMC1140436] [PubMed: 15897456]
  9. Hoda JC, Zaghetto F, Koschak A, Striessnig J. Congenital stationary night blindness type 2 mutations S229P, G369D, L1068P, and W1440X alter channel gating or functional expression of Ca(v)1.4 L-type Ca2+ channels. J Neurosci. 2005;25:252–9. [PubMed: 15634789]
  10. Hoda JC, Zaghetto F, Singh A, Koschak A, Striessnig J. Effects of congenital stationary night blindness type 2 mutations R508Q and L1364H on Cav1.4 L-type Ca2+ channel function and expression. J Neurochem. 2006;96:1648–58. [PubMed: 16476079]
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Suggested Reading

  1. Dryja TP. Retinitis pigmentosa and stationary night blindness. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 235. Available online. Accessed 12-11-13.
  2. Miyake Y. Congenital stationary blindness. In: Heckenlively JR, Arden GB, eds. Principles and Practice of Clinical Electrophysiology of Vision. 2 ed. Cambridge, MA: MIT Press; 2006:829-39.

Chapter Notes

Acknowledgments

The authors would like to thank Linda MacLaren and Karen McElligott for years of service to the Mennonite community affected with CSNB2A.

Author History

N Torben Bech-Hansen, PhD; University of Calgary, Canada (2007-2012)
Kym M Boycott, PhD, MD (2007-present)
Ian M MacDonald, MD, CM (2007-present)
Yves Sauvé, PhD (2007-present)

Revision History

  • 26 April 2012 (me) Comprehensive update posted live
  • 16 January 2008 (me) Review posted to live Web site
  • 9 August 2007 (im) Original submission
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