Mutation analysis of NR2E3 and NRL genes in Enhanced S Cone Syndrome.
Ten new and seventeen previously reported Enhanced S Cone Syndrome (ESCS) subjects were used to search for genetic heterogeneity. All subjects were diagnosed with ESCS on the basis of clinical, psychophysical and/or electroretinography testing using published criteria. Mutation analysis was performed on the NR2E3 nuclear receptor gene by single strand conformation analysis and direct sequencing, which revealed either homozygous (N=13) or compound heterozygous (N=11) mutations in 24 subjects (89%), heterozygous mutations in 2 subjects (7%) and no mutations in 1 subject (4%). Fifteen different mutations were identified, including six not previously reported. The subject (Patient A) with no detected NR2E3 mutation had features not usually associated with ESCS, in particular moderate rod photoreceptor function in peripheral retina and an abnormally thick retinal nerve fibre layer. Mutation analysis of the NRL, CRX, NR1D1 and THRB genes in this individual revealed a heterozygous one base-pair insertion in exon 2 of the NRL gene, which results in a predicted truncation of the NRL protein. Loss-of-function NRL alleles have not been described previously in humans, but since the same mutation was present in unaffected family members, it raises the possibility that the abnormal ESCS phenotype in Patient A may result from a digenic mechanism, with a heterozygous NRL mutation and a mutation in another unknown gene.
MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom. alan.wright@hgu.mrc.uk
Alan F
AF
Wright
Adam C
AC
Reddick
Sharon B
SB
Schwartz
Julie S
JS
Ferguson
Tomas S
TS
Aleman
Ulrich
U
Kellner
Bernhard
B
Jurklies
Andreas
A
Schuster
Eberhart
E
Zrenner
Bernd
B
Wissinger
Alan
A
Lennon
Xinhua
X
Shu
Artur V
AV
Cideciyan
Edwin M
EM
Stone
Samuel G
SG
Jacobson
Anand
A
Swaroop
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004596:Electroretinography; D005091:Exons / Q000235:genetics; D005128:Eye Diseases / Q000235:genetics* / Q000503:physiopathology; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D057093:Orphan Nuclear Receptors; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D005136:Eye Proteins; C403073:NR2E3 protein, human; C490037:NRL protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors