Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation.

[aniridia]

Autosomal-dominant idiopathic infantile nystagmus has been linked to 6 p 12 (OMIM 164100 ), 7 p 11 .2 (OMIM 608345 ) and 13 q 31 -q 33 (OMIM 193003 ). PAX 6 (11 p 13 , OMIM 607108 ) mutations can also cause autosomal-dominant nystagmus , typically in association with aniridia or iris hypoplasia . We studied a large multigenerational white British family with autosomal-dominant nystagmus , normal irides and presenile cataracts . An SNP-based genome-wide analysis revealed a linkage to a 13 .4 -MB region on chromosome 11 p 13 with a maximum lod score of 2 .93 . A mutation analysis of the entire coding region and splice junctions of the PAX 6 gene revealed a novel heterozygous missense mutation (c .227 C >G ) that segregated with the phenotype and is predicted to result in the amino-acid substitution of proline by arginine at codon 76 p .(P 76 R ). The amino-acid variation p .(P 76 R ) within the paired box domain is likely to destabilise the protein due to steric hindrance as a result of the introduction of a polar and larger amino acid . Eye movement recordings showed a significant intrafamilial variability of horizontal , vertical and torsional nystagmus . High -resolution in vivo imaging of the retina using optical coherence tomography (OCT ) revealed features of foveal hypoplasia , including rudimentary foveal pit , incursion of inner retinal layers , short photoreceptor outer segments and optic nerve hypoplasia . Thus , this study presents a family that segregates a PAX 6 mutation with nystagmus and foveal hypoplasia in the absence of iris abnormalities . Moreover , it is the first study showing detailed characteristics using eye movement recordings of autosomal-dominant nystagmus in a multigenerational family with a novel PAX 6 mutation .

Diseases
Validation

Diseases presenting "heterozygous missense mutation" symptom

alexander disease

aniridia

benign recurrent intrahepatic cholestasis

cadasil

epidermolysis bullosa simplex

kallmann syndrome

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