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

J Graw, N Klopp, T Illig, MN Preising… - Graefe's Archive for Clinical …, 2006 - Springer
J Graw, N Klopp, T Illig, MN Preising, B Lorenz
Graefe's Archive for Clinical and Experimental Ophthalmology, 2006Springer
Background 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. Methods 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 …
Background
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.
Methods
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.
Results
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.
Conclusion
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.
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