Congenital cataract and macular hypoplasia in humans associated with a de novo mutation in CRYAA and compound heterozygous mutations in P

  • Jochen Graw
  • Norman Klopp
  • Thomas Illig
  • Markus N. Preising
  • Birgit Lorenz



An isolated form of congenital cataract associated with macular hypoplasia and a generally hypopigmented fundus in infancy was observed in a German family. To test the hypothesis that a de-novo mutation had occurred in one of the parental germ lines, a functional candidate gene approach was applied.


The family was carefully examined by a senior paediatric ophthalmologist according to routine procedures (slit lamp, funduscopy, ERG). Blood was taken from the proband and his parents, genomic DNA was isolated and some candidate genes for cataract (CRYAA, CRYBB2, GJA8) or macular hypoplasia (OA1, P) or both (PAX6) were analyzed.


The proband showed bilateral cataracts at the age of 4 months; the fundus appeared pale, the optic disc grayish, and macular reflexes were absent. After cataract surgery, the nystagmus persisted, and a control ERG at age 9 years showed essentially normal scotopic and photopic wave forms. An infectious aetiology as well as galactosemia were excluded. However, a heterozygous mutation was found in the proband in exon 1 of CRYAA (62 C→T), which leads to an exchange from Arg to Leu at amino acid position 21 (R21L). This sequence alteration was not found in the parents and in 96 randomly selected DNA samples from ophthalmologically normal individuals of the KORA S4 study population. In addition, two heterozygous mutations in P were identified (R419Q and A481T); one of both was present in each of the unaffected parents.


Based upon the unique finding of the mutation and the expression of CRYAA in the lens, this R21L mutation in the CRYAA is considered to be causative for the dominant cataract phenotype. Moreover, the macular hypoplasia has to be considered a concerted interaction with compound heterozygous mutations in the P gene manifesting a mild form of oculocutaneous albinism. Nevertheless, this combination is rare and future studies will focus on identifying similar phenotypes.


Cataract CRYAA Mutation Human Macular Hypoplasia 



Various forms of galactosemia were ruled out biochemically by Professor Y. Shin, University Children´s Hospital Munich, Germany. An infectious etiology was ruled out at the Institute of Medical Microbiology, University of Regensburg (Head: Professor Dr. H. Wolf). We thank Dr. Jack Favor (Neuherberg) for critical comments on the manuscript.

The excellent technical assistance of Birgit Langer and Günther Schuch (Regensburg) and of Erika Bürkle, Michaela Bunge, Sabrina Hauser and Monika Stadler (GSF Neuherberg) is gratefully acknowledged. Oligonucleotides were synthesized by Utz Linzner, GSF-Institute of Experimental Genetics.

The KORA Group consists of H.E. Wichmann (speaker), H. Löwel, C. Meisinger, T. Illig, R. Holle, J. John and their co-workers who are responsible for the design and conduct of the KORA studies.

The KORA research platform (KORA: Cooperative Research in the Region of Augsburg) was initiated and financed by the GSF - National Research Center for Environment and Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria; part of this work was also supported by the National Genome Research Network (NGFN).


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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Jochen Graw
    • 1
  • Norman Klopp
    • 2
  • Thomas Illig
    • 2
  • Markus N. Preising
    • 3
  • Birgit Lorenz
    • 3
  1. 1.GSF-National Research Center for Environment and HealthInstitute of Developmental GeneticsNeuherbergGermany
  2. 2.GSF-National Research Center for Environment and HealthInstitute of EpidemiologyNeuherbergGermany
  3. 3.Department of Paediatric Ophthalmology, Strabismology and Ophthalmogenetics, KlinikumUniversity of RegensburgRegensburgGermany

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