Skip to main content

Advertisement

SpringerLink
Log in

Potential involvement of more than one locus in trait manifestation for individuals with Leber congenital amaurosis

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Leber congenital amaurosis (LCA) is a clinically and genetically heterogeneous retinal dystrophy. The causes of LCA have been unraveled partially at the molecular level. At least 14 genes have been reported that, when mutated, result in LCA. To understand the roles of the known genes in LCA, a group of outbred subjects from 60 apparently either recessive families, with one or more affected individuals, or isolated patients were evaluated. One affected individual from each family underwent comprehensive mutational analysis by direct DNA sequencing of all coding regions and splice junctions of 13 LCA genes. Mutations were identified in 70% of individuals. CEP290 made the largest contribution to the identified mutations, providing 43% of those mutant alleles. We identified seven families in which affected individuals with two mutant alleles, sufficient to cause disease, had an additional mutation at a second LCA locus. Our findings suggest that mutational load can be important to penetrance of the LCA phenotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abd-El-Barr MM, Sykoudis K, Andrabi S, Eichers ER, Pennesi ME, Tan PL, Wilson JH, Katsanis N, Lupski JR, Wu SM (2007) Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet–Biedl syndrome. Vision Res 47(27):3394–3407

    Article  CAS  PubMed  Google Scholar 

  • Akey DT, Zhu X, Dyer M, Li A, Sorensen A, Blackshaw S, Fukuda-Kamitani T, Daiger SP, Craft CM, Kamitani T, Sohocki MM (2002) The inherited blindness associated protein AIPL1 interacts with the cell cycle regulator protein NUB1. Hum Mol Genet 11(22):2723–2733

    Article  CAS  PubMed  Google Scholar 

  • Badano JL, Katsanis N (2002) Beyond Mendel: an evolving view of human genetic disease transmission. Nat Rev Genet 3(10):779–789

    Article  CAS  PubMed  Google Scholar 

  • Badano JL, Leitch CC, Ansley SJ, May-Simera H, Lawson S, Lewis RA, Beales PL, Dietz HC, Fisher S, Katsanis N (2006a) Dissection of epistasis in oligogenic Bardet–Biedl syndrome. Nature 439(7074):326–330

    Article  CAS  PubMed  Google Scholar 

  • Badano JL, Mitsuma N, Beales PL, Katsanis N (2006b) The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7:125–148

    Article  CAS  PubMed  Google Scholar 

  • Booij JC, Florijn RJ, ten Brink JB, Loves W, Meire F, van Schooneveld MJ, de Jong PT, Bergen AA (2005) Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. J Med Genet 42(11):e67

    Article  CAS  PubMed  Google Scholar 

  • Brancati F, Barrano G, Silhavy JL, Marsh SE, Travaglini L, Bielas SL, Amorini M, Zablocka D, Kayserili H, Al-Gazali L, Bertini E, Boltshauser E, D’Hooghe M, Fazzi E, Fenerci EY, Hennekam RC, Kiss A, Lees MM, Marco E, Phadke SR, Rigoli L, Romano S, Salpietro CD, Sherr EH, Signorini S, Stromme P, Stuart B, Sztriha L, Viskochil DH, Yuksel A, Dallapiccola B, Valente EM, Gleeson JG (2007) CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. Am J Hum Genet 81(1):104–113

    Article  CAS  PubMed  Google Scholar 

  • Chiang PW, Spector E, McGregor TL (2009) Evidence suggesting digenic inheritance of Waardenburg syndrome type II with ocular albinism. Am J Med Genet A 149(12):2739–2744

    Google Scholar 

  • Coppieters F, Casteels I, Meire F, De Jaegere S, Hooghe S, van Regemorter N, Van Esch H, Matuleviciene A, Nunes L, Meersschaut V, Walraedt S, Standaert L, Coucke P, Hoeben H, Kroes HY, Vande Walle J, de Ravel T, Leroy BP, De Baere E (2010) Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes. Hum Mutat Aug 5 [Epub ahead of print]

  • Cremers FP, van den Hurk JA, den Hollander AI (2002) Molecular genetics of Leber congenital amaurosis. Hum Mol Genet 11(10):1169–1176

    Article  CAS  PubMed  Google Scholar 

  • den Hollander AI, Johnson K, de Kok YJ, Klebes A, Brunner HG, Knust E, Cremers FP (2001) CRB1 has a cytoplasmic domain that is functionally conserved between human and drosophila. Hum Mol Genet 10(24):2767–2773

    Article  Google Scholar 

  • den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, Cremers FP (2006) Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am J Hum Genet 79(3):556–561

    Article  Google Scholar 

  • den Hollander AI, Roepman R, Koenekoop RK, Cremers FP (2008) Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 27(4):391–419

    Article  Google Scholar 

  • Dharmaraj SR, Silva ER, Pina AL, Li YY, Yang JM, Carter CR, Loyer MK, El-Hilali HK, Traboulsi EK, Sundin OK, Zhu DK, Koenekoop RK, Maumenee IH (2000) Mutational analysis and clinical correlation in Leber congenital amaurosis. Ophthalmic Genet 21(3):135–150

    CAS  PubMed  Google Scholar 

  • Ebermann I, Phillips JB, Liebau MC, Koenekoop RK, Schermer B, Lopez I, Schafer E, Roux AF, Dafinger C, Bernd A, Zrenner E, Claustres M, Blanco B, Nurnberg G, Nurnberg P, Ruland R, Westerfield M, Benzing T, Bolz HJ (2010) PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome. J Clin Invest 120(6):1812–1823

    Article  CAS  PubMed  Google Scholar 

  • Eichers ER, Lewis RA, Katsanis N, Lupski JR (2004) Triallelic inheritance: a bridge between Mendelian and multifactorial traits. Ann Med 36(4):262–272

    Article  CAS  PubMed  Google Scholar 

  • Gerber S, Perrault I, Hanein S, Barbet F, Ducroq D, Ghazi I, Martin-Coignard D, Leowski C, Homfray T, Dufier JL, Munnich A, Kaplan J, Rozet JM (2001) Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Eur J Hum Genet 9(8):561–571

    Article  CAS  PubMed  Google Scholar 

  • Hanein S, Perrault I, Gerber S, Tanguy G, Barbet F, Ducroq D, Calvas P, Dollfus H, Hamel C, Lopponen T, Munier F, Santos L, Shalev S, Zafeiriou D, Dufier JL, Munnich A, Rozet JM, Kaplan J (2004) Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype–phenotype correlations as a strategy for molecular diagnosis. Hum Mutat 23(4):306–317

    Article  CAS  PubMed  Google Scholar 

  • Hichri H, Stoetzel C, Laurier V, Caron S, Sigaudy S, Sarda P, Hamel C, Martin-Coignard D, Gilles M, Leheup B, Holder M, Kaplan J, Bitoun P, Lacombe D, Verloes A, Bonneau D, Perrin-Schmitt F, Brandt C, Besancon AF, Mandel JL, Cossee M, Dollfus H (2005) Testing for triallelism: analysis of six BBS genes in a Bardet–Biedl syndrome family cohort. Eur J Hum Genet 13(5):607–616

    Article  CAS  PubMed  Google Scholar 

  • Ito S, Nakamura M, Nuno Y, Ohnishi Y, Nishida T, Miyake Y (2004) Novel complex GUCY2D mutation in Japanese family with cone-rod dystrophy. Invest Ophthalmol Vis Sci 45(5):1480–1485

    Article  PubMed  Google Scholar 

  • Kajiwara K, Berson EL, Dryja TP (1994) Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 264(5165):1604–1608

    Google Scholar 

  • Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ, Davidson WS, Beales PL, Lupski JR (2001) Triallelic inheritance in Bardet–Biedl syndrome, a Mendelian recessive disorder. Science 293(5538):2256–2259

    Article  CAS  PubMed  Google Scholar 

  • Khanna H, Davis EE, Murga-Zamalloa CA, Estrada-Cuzcano A, Lopez I, den Hollander AI, Zonneveld MN, Othman MI, Waseem N, Chakarova CF, Maubaret C, Diaz-Font A, Macdonald I, Muzny DM, Wheeler DA, Morgan M, Lewis LR, Logan CV, Tan PL, Beer MA, Inglehearn CF, Lewis RA, Jacobson SG, Bergmann C, Beales PL, Attie-Bitach T, Johnson CA, Otto EA, Bhattacharya SS, Hildebrandt F, Gibbs RA, Koenekoop RK, Swaroop A, Katsanis N (2009) A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nat Genet 41(6):739–745

    Article  CAS  PubMed  Google Scholar 

  • Koenekoop RK (2004) An overview of Leber congenital amaurosis: a model to understand human retinal development. Surv Ophthalmol 49(4):379–398

    Article  PubMed  Google Scholar 

  • Lewis RA (ed) (1988) Juvenile hereditary macular dystrophies. In: Retinal dystrophies and degenerations. Raven Press, New York

  • Lewis RA, Shroyer NF, Singh N, Allikmets R, Hutchinson A, Li Y, Lupski JR, Leppert M, Dean M (1999) Genotype/phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet 64(2):422–434

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Wang H, Peng J, Gibbs RA, Lewis RA, Lupski JR, Mardon G, Chen R (2009) Mutation survey of known LCA genes and loci in the Saudi Arabian population. Invest Ophthalmol Vis Sci 50(3):1336–1343

    Article  PubMed  Google Scholar 

  • Lotery AJ, Namperumalsamy P, Jacobson SG, Weleber RG, Fishman GA, Musarella MA, Hoyt CS, Heon E, Levin A, Jan J, Lam B, Carr RE, Franklin A, Radha S, Andorf JL, Sheffield VC, Stone EM (2000) Mutation analysis of 3 genes in patients with Leber congenital amaurosis. Arch Ophthalmol 118(4):538–543

    CAS  PubMed  Google Scholar 

  • Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP (1998) Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis. Proc Natl Acad Sci USA 95(6):3088–3093

    Article  CAS  PubMed  Google Scholar 

  • Perrault I, Hanein S, Gerber S, Barbet F, Ducroq D, Dollfus H, Hamel C, Dufier JL, Munnich A, Kaplan J, Rozet JM (2004) Retinal dehydrogenase 12 (RDH12) mutations in Leber congenital amaurosis. Am J Hum Genet 75(4):639–646

    Article  CAS  PubMed  Google Scholar 

  • Perrault I, Delphin N, Hanein S, Gerber S, Dufier JL, Roche O, Defoort-Dhellemmes S, Dollfus H, Fazzi E, Munnich A, Kaplan J, Rozet JM (2007) Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat 28(4):416

    Article  PubMed  Google Scholar 

  • Perrault I, Hanein S, Gerard X, Delphin N, Fares-Taie L, Gerber S, Pelletier V, Merce E, Dollfus H, Puech B, Defoort-Dhellemmes S, Petersen MD, Zafeiriou D, Munnich A, Kaplan J, Roche O, Rozet JM (2010) Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat 31(3):E1241–E1250

    Article  CAS  PubMed  Google Scholar 

  • Shroyer NF, Lewis RA, Allikmets R, Singh N, Dean M, Leppert M, Lupski JR (1999) The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: from monogenic to multifactorial. Vis Res 39(15):2537–2544

    Article  CAS  PubMed  Google Scholar 

  • Shroyer NF, Lewis RA, Yatsenko AN, Lupski JR (2001a) Null missense ABCR (ABCA4) mutations in a family with Stargardt disease and retinitis pigmentosa. Invest Ophthalmol Vis Sci 42(12):2757–2761

    CAS  PubMed  Google Scholar 

  • Shroyer NF, Lewis RA, Yatsenko AN, Wensel TG, Lupski JR (2001b) Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. Hum Mol Genet 10(23):2671–2678

    Article  CAS  PubMed  Google Scholar 

  • Simonelli F, Ziviello C, Testa F, Rossi S, Fazzi E, Bianchi PE, Fossarello M, Signorini S, Bertone C, Galantuomo S, Brancati F, Valente EM, Ciccodicola A, Rinaldi E, Auricchio A, Banfi S (2007) Clinical and molecular genetics of Leber’s congenital amaurosis: A multicenter study of Italian patients. Invest Ophthalmol Vis Sci 48(9):4284–4290

    Article  PubMed  Google Scholar 

  • Sohocki MM, Browne SJ, Sullivan LS, Blackshaw S, Cepko CL, Payne AM, Bhattacharya SS, Khaliq S, Mehdi SQ, Birch DG, Harrison WR, Elder FF, Heckenlively JR, Daiger SP (2000a) Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. Am J Ophthalmol 129(6):834–835

    Article  Google Scholar 

  • Sohocki MM, Perrault I, Leroy BP, Payne AM, Dharmaraj S, Bhattacharya SS, Kaplan J, Maumenee IH, Koenekoop R, Meire FM, Birch DG, Heckenlively JR, Daiger SP (2000b) Prevalence of AIPL1 mutations in inherited retinal degenerative disease. Mol Genet Metab 70(2):142–150

    Article  CAS  PubMed  Google Scholar 

  • Stone EM (2007) Leber congenital amaurosis—a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson memorial lecture. Am J Ophthalmol 144(6):791–811

    Article  CAS  PubMed  Google Scholar 

  • Swaroop A, Wang QL, Wu W, Cook J, Coats C, Xu S, Chen S, Zack DJ, Sieving PA (1999) Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function. Hum Mol Genet 8(2):299–305

    Article  CAS  PubMed  Google Scholar 

  • Thompson DA, Janecke AR, Lange J, Feathers KL, Hubner CA, McHenry CL, Stockton DW, Rammesmayer G, Lupski JR, Antinolo G, Ayuso C, Baiget M, Gouras P, Heckenlively JR, den Hollander A, Jacobson SG, Lewis RA, Sieving PA, Wissinger B, Yzer S, Zrenner E, Utermann G, Gal A (2005) Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle. Hum Mol Genet 14(24):3865–3875

    Article  CAS  PubMed  Google Scholar 

  • Tsang WY, Bossard C, Khanna H, Peranen J, Swaroop A, Malhotra V, Dynlacht BD (2008) CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease. Dev Cell 15(2):187–197

    Article  CAS  PubMed  Google Scholar 

  • Wiszniewski W, Zaremba CM, Yatsenko AN, Jamrich M, Wensel TG, Lewis RA, Lupski JR (2005) ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. Hum Mol Genet 14(19):2769–2778

    Article  CAS  PubMed  Google Scholar 

  • Xu T, Yang Z, Vatta M, Rampazzo A, Beffagna G, Pilichou K, Scherer SE, Saffitz J, Kravitz J, Zareba W, Danieli GA, Lorenzon A, Nava A, Bauce B, Thiene G, Basso C, Calkins H, Gear K, Marcus F, Towbin JA (2010) Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 55(6):587–597

    Article  CAS  PubMed  Google Scholar 

  • Yzer S, Leroy BP, De Baere E, de Ravel TJ, Zonneveld MN, Voesenek K, Kellner U, Ciriano JP, de Faber JT, Rohrschneider K, Roepman R, den Hollander AI, Cruysberg JR, Meire F, Casteels I, van Moll-Ramirez NG, Allikmets R, van den Born LI, Cremers FP (2006) Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci 47(3):1167–1176

    Article  PubMed  Google Scholar 

  • Zernant J, Kulm M, Dharmaraj S, den Hollander AI, Perrault I, Preising MN, Lorenz B, Kaplan J, Cremers FP, Maumenee I, Koenekoop RK, Allikmets R (2005) Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles. Invest Ophthalmol Vis Sci 46(9):3052–3059

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful for willing participation and the continuing support of families who joined these efforts. This work was supported in part by National Eye Institute (NIH) R01EY018571to R.C. R.A.L. is a Senior Scientific Investigator of Research to Prevent Blindness, New York. Some of the early work reported here was supported in part by the Foundation Fighting Blindness, Owens Mills, MD.

Author information

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 604B, Houston, TX, USA

    Wojciech Wiszniewski & James R. Lupski

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    Richard Alan Lewis, Graeme Mardon & Rui Chen

  3. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Richard Alan Lewis & James R. Lupski

  4. Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA

    Richard Alan Lewis & Graeme Mardon

  5. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Richard Alan Lewis

  6. Human Genome Center, Baylor College of Medicine, Houston, TX, USA

    Jianlan Peng & Rui Chen

  7. Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA

    Graeme Mardon

  8. Department of Pathology, Baylor College of Medicine, Houston, TX, USA

    Graeme Mardon

  9. Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA

    Graeme Mardon & Rui Chen

  10. Texas Children’s Hospital, Houston, TX, USA

    James R. Lupski

  11. Department of Pediatrics and Department of Internal Medicine, Wayne State University, Detroit, MI, USA

    David W. Stockton

  12. Division of Genetic and Metabolic Disorders, Children’s Hospital of Michigan, Detroit, MI, USA

    David W. Stockton

Authors
  1. Wojciech Wiszniewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard Alan Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David W. Stockton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jianlan Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Graeme Mardon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rui Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. James R. Lupski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James R. Lupski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wiszniewski, W., Lewis, R.A., Stockton, D.W. et al. Potential involvement of more than one locus in trait manifestation for individuals with Leber congenital amaurosis. Hum Genet 129, 319–327 (2011). https://doi.org/10.1007/s00439-010-0928-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-010-0928-y

Keywords

Search

Navigation