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Various phenotypic expressions of familial aniridia with a PAX6 mutation
  1. K NEGISHI
  1. Department of Ophthalmology
  2. National Saitama Hospital
  3. Saitama 351-0102, Japan
  4. Department of Ophthalmology
  5. National Children’s Hospital
  6. Tokyo 154, Japan
  1. N AZUMA,
  2. M YAMADA
  1. Department of Ophthalmology
  2. National Saitama Hospital
  3. Saitama 351-0102, Japan
  4. Department of Ophthalmology
  5. National Children’s Hospital
  6. Tokyo 154, Japan
  1. Kazuno Negishi, MD, Department of Ophthalmology, Toden Hospital, 9-2, Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan.

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Editor,—Aniridia is an uncommon congenital bilateral panocular disorder characterised by complete or partial absence of the iris and foveal hypoplasia. Aniridia can appear in a high penetrance form associated with other ocular anomalies such as keratopathy, foveal hypoplasia, cataract, ectopia lentis, and glaucoma.1 Recent studies showed that aniridia is caused by mutation of the PAX6gene,2-4 which controls early events in cerebral and ocular formation.4-7 We present a pedigree with various clinical findings of aniridia in which a mutation of thePAX6 gene was identified.

CASE REPORTS

The family tree is shown in Figure 1A. Case I-1 is a 52 year old man with visual impairment and nystagmus. He had cataract from an early age (the detail was unknown). His vision was right eye finger counting at 20 cm and left eye 0.01; eye examination revealed bilateral partial aniridia, dense cataract, corneal pannus, and foveal hypoplasia (Fig2A, B). His cataracts were removed and posterior chamber intraocular lenses were implanted at age 52. One son, II-1, is 16 years old with nystagmus, visual acuities of right eye 0.3 and left eye 0.2, bilateral corneal pannus, iris thinning, and mild foveal hypoplasia; his lenses were clear (Fig 2 C, D). Another son, II-2, is 14 years old with nystagmus, visual acuities of right eye 0.2 and left eye 0.2, bilateral iris thinning, corneal pannus, and mild foveal hypoplasia; his lenses were clear (Fig 2 E, F). Case II-3 is a 13 year old male with nystagmus, visual acuities of right eye 0.3 and left eye 0.2, corneal pannus, partial aniridia, zonular cataracts, and foveal hypoplasia (Fig2 G, H). All affected patients were normal in size for age and had normal intelligence and karyotype (46XY). We analysed genomic DNA isolated from leucocytes of patients and family members. Genomic DNA representing 14 exons for the PAX6 gene was amplified by polymerase chain reaction (PCR) and subjected to SSCP analyses.8 An abnormal pattern for exon 11 was identified indicating a heterozygous mutation in all affected patients but not in unaffected members of the immediate family or in over 100 normal individuals (Fig 1A) Sequencing analysis demonstrated a deletion of a single nucleotide at the 1434th position (in this study, the numbers of the nucleotide and amino acid were based on the sequence of GenBank Accession No M93650) (Fig 1B). No other changes in nucleotide sequence were detected.

Figure 1

(A) PCR-SSCP analysis of exon 11 reveals a band shift in patients I-1, II-1, II-2, and II-3. (B) Sequencing of the normal and mutant alleles of I-1 identifies a single base deletion at nucleotide 1434 that causes a translational frameshift in the proline, serine, and threonine (PST) domain. Other affected members had the same mutation.

Figure 2

Photograph of anterior segment of case I-1 (A, right eye; B, left eye) with corneal pannus, absent iris, dense cataract; case II-1 (C, right eye; D, left eye) with corneal pannus and iris thinning; case II-2 (E, right eye; F, left eye) with corneal pannus, partially absent iris; and case II-3 (G, right eye; H, left eye) with corneal pannus, partially absent iris, and suture cataract.

COMMENT

The human PAX6 gene is 422 amino acids long and has paired box and homeobox DNA binding domains. These are separated by a 78 amino acid linker segment and followed by a 152 amino acid C-terminal region rich in proline, serine, and threonine (PST domain). In our cases, the PAX6 mutation is predicted to result in amino acid substitutions from the 339th position and a truncation at the 344th position, resulting in a truncated protein product that ultimately excludes part of the PST domain. Truncated proteins generally tend to be degraded, thus haploinsufficiency of PAX6 was believed to cause aniridia phenotype. However, biochemical assay recently indicated that truncation mutations in the PST transactivation region ofPAX6 result in dominant negative mutants.9 A truncated protein of nearly normal size may function for a short time.

The affected individuals in this family had a wide variation of phenotypes, including thinning and the absence of the iris, various features of cataract, and foveal hypoplasia. Hittneret al10 11 described suspected familial aniridia cases in which expressivity was variable as was seen in our cases. Probably many modifiers affect a variety of phenotypic expression in a pedigree with the samePAX6 mutation. Because thePAX6 gene is a master control gene,12 it may control numerous downstream genes, whose expression pattern probably is slightly different among each individual. Affected patients may also reflect modifiers unlinked to the PAX6 gene cascade, stochastic effects, or environmental factors. The fact that there was little difference in the phenotypes between two eyes of each individual in a pedigree also supports this hypothesis.

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