FOXE3 plays a significant role in autosomal recessive microphthalmia.
FOXE3 forkhead transcription factor is essential to lens development in vertebrates. The eyes of Foxe3/foxe3-deficient mice and zebrafish fail to develop normally. In humans, autosomal dominant and recessive mutations in FOXE3 have been associated with variable phenotypes including anterior segment anomalies, cataract, and microphthalmia. We undertook sequencing of FOXE3 in 116 probands with a spectrum of ocular defects ranging from anterior segment dysgenesis and cataract to anophthalmia/microphthalmia. Recessive mutations in FOXE3 were found in four of 26 probands affected with bilateral microphthalmia (15% of all bilateral microphthalmia and 100% of consanguineous families with this phenotype). FOXE3-positive microphthalmia was accompanied by aphakia and/or corneal defects; no other associated systemic anomalies were observed in FOXE3-positive families. The previously reported c.720C > A (p.C240X) nonsense mutation was identified in two additional families in our sample and therefore appears to be recurrent, now reported in three independent microphthalmia families of varied ethnic backgrounds. Several missense variants were identified at varying frequencies in patient and control groups with some apparently being race-specific, which underscores the importance of utilizing race/ethnicity-matched control populations in evaluating the relevance of genetic screening results. In conclusion, FOXE3 mutations represent an important cause of nonsyndromic autosomal recessive bilateral microphthalmia.
Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Linda M
LM
Reis
Rebecca C
RC
Tyler
Adele
A
Schneider
Tanya
T
Bardakjian
Joan M
JM
Stoler
Serge B
SB
Melancon
Elena V
EV
Semina
D000595:Amino Acid Sequence; D000818:Animals; D001035:Aphakia / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017124:Conserved Sequence; D003315:Cornea / Q000002:abnormalities; D017931:DNA Primers / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D005808:Genes, Recessive; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008850:Microphthalmos / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; C404285:FOXE3 protein, human; D051858:Forkhead Transcription Factors