Skip to main content
SpringerLink
Log in

Molecular Mechanisms of Inherited Disease

  • Reference work entry
  • First Online:
Albert and Jakobiec's Principles and Practice of Ophthalmology

  • 144 Accesses

Abstract

DNA mutations occurring in genes may result in the formation of a defective gene product. If the normal protein product of a mutated gene is necessary for a critical biologic function, then an alteration of the normal phenotype may occur. Many changes in phenotype are considered normal variations among humans, for example, brown hair instead of blond hair. However, some changes produce phenotypes that seriously affect health; these are the major focus of study in clinical genetics laboratories. This chapter describes general principles of disease causing mechanisms in humans.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 5,499.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 6,499.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Read AP. Pax genes-paired feet in three camps. Nat Genet. 1995;9:333–4.

    Article  CAS  PubMed  Google Scholar 

  2. Ton CCT, Hirvonen H, Mira H, et al. Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell. 1991;67:1059–74.

    Article  CAS  PubMed  Google Scholar 

  3. Richardson J, Cvekl A, Wistow G. Pax-6 is essential for lens-specific expression of zeta-crystallin. Proc Natl Acad Sci U S A. 1995;92:4676–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gregory-Evans CY, Wang X, Wasan KM, Zhao J, Metcalfe AL, Gregory-Evans K. Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects. J Clin Invest. 2014;124(1):111–6.

    Article  CAS  PubMed  Google Scholar 

  5. Glaser T, Jepeal L, Edwards JG, et al. PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet. 1994;7:463–71.

    Article  CAS  PubMed  Google Scholar 

  6. Hanson IM, Fletcher JM, Jordon T, et al. Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet. 1994;6:168–73.

    Article  CAS  PubMed  Google Scholar 

  7. Mirzayans F, Pearce WG, MacDonald IM, et al. Mutation of the PAX6 gene in patients with autosomal dominant keratitis. Am J Hum Genet. 1995;57:539–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Davis A, Cowell JK. Mutations in the PAX6 gene in patients with hereditary aniridia. Hum Mol Genet. 1993;2:2093–7.

    Article  CAS  PubMed  Google Scholar 

  9. Hjalt TA, Semina EV. Current molecular understanding of Axenfeld–Rieger syndrome. Expert Rev Mol Med. 2005;7:1–17.

    Article  PubMed  Google Scholar 

  10. Sato U, Kitanaka S, Sekine T, et al. Functional characterization of LMX1B mutations associated with nail-patella syndrome. Pediatr Res. 2005;57:783–8.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang HZ, Li P, Wang D, et al. FOXC1 gene deletion is associated with eye anomalies in ring chromosome 6. Am J Med Genet A. 2004;124:280–7.

    Article  Google Scholar 

  12. Kohlhase J, Chitayat D, Kotzot D, et al. SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders. Hum Mutat. 2005;26:176–83.

    Article  CAS  PubMed  Google Scholar 

  13. Ferre M, Amati-Bonneau P, Tourmen Y, et al. eOPA1: an online database for OPA1 mutations. Hum Mutat. 2005;25:423–8.

    Article  CAS  PubMed  Google Scholar 

  14. Freund CL, Gregory-Evans CY, Furukawa T, et al. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell. 1997;91:543–53.

    Article  CAS  PubMed  Google Scholar 

  15. Tassabehji M, Read AP, Newton VE, et al. Waardenburg’s syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature. 1992;355:635–6.

    Article  CAS  PubMed  Google Scholar 

  16. Friend SH, Dryja TP, Weinberg RA. Oncogenes and tumor-suppressing genes. N Engl J Med. 1988;318:618–22.

    Article  CAS  PubMed  Google Scholar 

  17. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323–30.

    Article  CAS  PubMed  Google Scholar 

  18. Dryja TP, Cavenee W, White R, et al. Homozygosity of chromosome 13 in retinoblastoma. N Engl J Med. 1984;310:550–3.

    Article  CAS  PubMed  Google Scholar 

  19. Knudson AG Jr. Genetics of human cancer. Annu Rev Genet. 1986;20:231–51.

    Article  PubMed  Google Scholar 

  20. Herskowitz I. Functional inactivation of genes by dominant negative mutations [review]. Nature. 1987;329:219–322.

    Article  CAS  PubMed  Google Scholar 

  21. Moller HU. Inter-familial variability and intra-familial similarities of granular corneal dystrophy Groenouw type I with respect to biomicroscopical appearance and symptomatology. Act Ophthalmol. 1989;67:669–77.

    Article  CAS  Google Scholar 

  22. Klintworth GK. Lattice corneal dystrophy: an inherited variety of amyloidosis restricted to the cornea. Am J Pathol. 1967;50:371–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Folberg R, Alfonso E, Croxatto JO, et al. Clinically atypical granular corneal dystrophy with pathologic features of lattice-like amyloid deposits. Ophthalmology. 1988;95:46–51.

    Article  CAS  PubMed  Google Scholar 

  24. Rosenwasser GO, Sucheski BM, Rosa N, et al. Phenotypic variation in combined granular-lattice (Avellino) corneal dystrophy. Arch Ophthalmol. 1993;111:1546–52.

    Article  CAS  PubMed  Google Scholar 

  25. Kuchle M, Green WR, Volcker HE, et al. Reevaluation of corneal dystrophies of Bowman’s layer and the anterior stroma (Reis–Bücklers and Thiel–Behnke types): a light and electron microscopic study of eight corneas and a review of the literature. Cornea. 1995;14:333–54.

    CAS  PubMed  Google Scholar 

  26. Munier FL, Korvatska E, Djemai A, et al. Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet. 1997;15:247–51.

    CAS  PubMed  Google Scholar 

  27. El Kochairi I, Letovanec I, Uffer S, et al. Systemic investigation of keratoepithelin deposits in TGFBI/BIGH3-related corneal dystrophy. Mol Vis. 2006;12:461–6.

    PubMed  Google Scholar 

  28. Nielsen NS, Poulsen ET, Lukassen MV, Chao Shern C, Mogensen EH, Weberskov CE, DeDionisio L, Schauser L, Moore TCB, Otzen DE, Hjortdal J, Enghild JJ. Biochemical mechanisms of aggregation in TGFBI-linked corneal dystrophies. Prog Retin Eye Res. 2020;77:100843.

    Article  CAS  PubMed  Google Scholar 

  29. Dryja TP, McGee TL, Reichel E, et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature. 1990;343:364–6.

    Article  CAS  PubMed  Google Scholar 

  30. Li T, Snyder WK, Olsson JE, et al. Transgenic mice carrying the dominant rhodopsin mutation P347S: evidence for defective vectorial transport of rhodopsin to the outer segments. Proc Natl Acad Sci U S A. 1996;93:14176–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wan A, Place E, Pierce EA, Comander J. Characterizing variants of unknown significance in rhodopsin: a functional genomics approach. Hum Mutat. 2019;40(8):1127–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stacey A, Bateman J, Choi T, et al. Perinatal lethal osteogenesis imperfecta in transgenic mice bearing an engineered mutant pro-alpha 1(I) collagen gene. Nature. 1988;332:131–6.

    Article  CAS  PubMed  Google Scholar 

  33. Richards RI, Sutherland GR. Dynamic mutations: a new class of mutations causing human disease. Cell. 1992;70:709–12.

    Article  CAS  PubMed  Google Scholar 

  34. Myers RH, Madden JJ, Teague JL, et al. Factors related to onset age of Huntington disease. Am J Hum Genet. 1982;34:481–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ranen NG, Stine OC, Abbott MH, et al. Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease. Am J Hum Genet. 1995;57:593–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Mooers BH, Logue JS, Berglund JA. The structural basis of myotonic dystrophy from the crystal structure of CUG repeats. Proc Natl Acad Sci U S A. 2005;102:16626–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Abou-Sleymane G, Chalmel F, Helmlinger D, et al. Polyglutamine expansion causes neurodegeneration by altering the neuronal differentiation program. Hum Mol Genet. 2006;15:691–703.

    Article  CAS  PubMed  Google Scholar 

  38. Clark RM, Bhaskar SS, Miyahara M, et al. Expansion of GAA trinucleotide repeats in mammals. Genomics. 2006;87:57–67.

    Article  CAS  PubMed  Google Scholar 

  39. Ranum LP, Day JW. Pathogenic RNA repeats: an expanding role in genetic disease. Trends Genet. 2004;20:506–12.

    Article  CAS  PubMed  Google Scholar 

  40. Fautsch MP, Wieben ED, Baratz KH, Bhattacharyya N, Sadan AN, Hafford-Tear NJ, Tuft SJ, Davidson AE. TCF4-mediated Fuchs endothelial corneal dystrophy: insights into a common trinucleotide repeat-associated disease. Prog Retin Eye Res. 2020;28:100883.

    Google Scholar 

  41. Hafford-Tear NJ, Tsai YC, Sadan AN, Sanchez-Pintado B, Zarouchlioti C, Maher GJ, Liskova P, Tuft SJ, Hardcastle AJ, Clark TA, Davidson AE. CRISPR/Cas9-targeted enrichment and long-read sequencing of the Fuchs endothelial corneal dystrophy-associated TCF4 triplet repeat. Genet Med. 2019;21(9):2092–102.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lewis A, Reik W. How imprinting centres work. Cytogenet Genome Res. 2006;113:81–9.

    Article  CAS  PubMed  Google Scholar 

  43. Kantor B, Shemer R, Razin A. The Prader–Willi/Angelman imprinted domain and its control center. Cytogenet Genome Res. 2006;113:300–5.

    Article  CAS  PubMed  Google Scholar 

  44. Ye H, Lan X, Liu Q, Zhang Y, Wang S, Zheng C, Di Y, Qiao T. Ocular findings and strabismus surgery outcomes in Chinese children with Angelman syndrome: three case reports. Medicine. 2019;98(51):e18077.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Spritz RA. Molecular genetics of oculocutaneous albinism. Hum Mol Genet. 1994;3:1469–75.

    Article  CAS  PubMed  Google Scholar 

  46. Spritz RA, Strunk K, Giebel LB, et al. Detection of mutations in the tyrosinase gene in a patient with type IA oculocutaneous albinism. N Engl J Med. 1990;322:1724–8.

    Article  CAS  PubMed  Google Scholar 

  47. Sauer CG, Gehrig A, Warneke-Wittstock R, et al. Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet. 1997;17:164–70.

    Article  CAS  PubMed  Google Scholar 

  48. Cukras C, Wiley HE, Jeffrey BG, Sen HN, Turriff A, Zeng Y, Vijayasarathy C, Marangoni D, Ziccardi L, Kjellstrom S, Park TK, Hiriyanna S, Wright JF, Colosi P, Wu Z, Bush RA, Wei LL, Sieving PA. Retinal AAV8-RS1 gene therapy for X-linked retinoschisis: initial findings from a phase I/IIa trial by intravitreal delivery. Mol Ther. 2018;26(9):2282–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. McGuire RE, Sullivan LS, Blanton SH, et al. X-linked dominate cone-rod degeneration: linkage mapping of a new locus for retinitis pigmentosa (RP15) to Xp22.13–p22.11. Am J Hum Genet. 1995;57:87–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kajiwara K, Berson EL, Dryja TP. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science. 1994;264:1604–8.

    Article  CAS  PubMed  Google Scholar 

  51. Kajiwara K, Hahn LB, Mukai S, et al. Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa. Nature. 1991;354:480–3.

    Article  CAS  PubMed  Google Scholar 

  52. Bascom RA, Schappert K, NcInnes RR. Cloning of the human and murine ROM1 genes: genomic organization and sequence conservation. Hum Mol Genet. 1993;2:385–91.

    Article  CAS  PubMed  Google Scholar 

  53. Strayve D, Makia MM, Kakakhel M, Sakthivel H, Conley SM, Al-Ubaidi MR, Naash MI. ROM1 contributes to phenotypic heterogeneity in PRPH2-associated retinal disease. Hum Mol Genet. 2020; https://doi.org/10.1093/hmg/ddaa160.

  54. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science. 1988;242:1427–30.

    Article  CAS  PubMed  Google Scholar 

  55. Brown MD, Voljavec AS, Lott MT, et al. Leber’s hereditary optic neuropathy; a model for mitochondrial neurodegenerative diseases. FASEB J. 1992;6:2791–9.

    Article  CAS  PubMed  Google Scholar 

  56. Cooke Bailey JN, Sobrin L, Pericak-Vance MA, Haines JL, Hammond CJ, Wiggs JL. Advances in the genomics of common eye diseases. Hum Mol Genet. 2013;22(R1):R59–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA

    Janey L. Wiggs

Authors
  1. Janey L. Wiggs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Janey L. Wiggs .

Editor information

Editors and Affiliations

  1. Casey Eye Institute, Oregon Health & Science, Portland, OR, USA

    Daniel M. Albert

  2. Department of Ophthalmology, Massachusetts Eye and Ear, Massachusetts General Hospital, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Joan W. Miller

  3. Department of Ophthalmology, University of Illinois College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Dimitri T. Azar

  4. Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA

    Lucy H. Young

Section Editor information

  1. Massachusetts Eye and Ear, Boston, USA

    Jason Comander

  2. Massachusetts Eye and Ear, Boston, USA

    Luk Vandenberghe

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Wiggs, J.L. (2022). Molecular Mechanisms of Inherited Disease. In: Albert, D.M., Miller, J.W., Azar, D.T., Young, L.H. (eds) Albert and Jakobiec's Principles and Practice of Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-030-42634-7_147

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-42634-7_147

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-42633-0

  • Online ISBN: 978-3-030-42634-7

  • eBook Packages: MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation