A novel PHOX2A/ARIX mutation in an Iranian family with congenital fibrosis of extraocular muscles type 2 (CFEOM2).
OBJECTIVE
To describe the clinical features of two affected members of an Iranian family with autosomal recessive congenital fibrosis of the extraocular muscles (CFEOM2) and to report their novel mutation in the PHOX2A/ARIX gene.


METHODS
Experimental study.


METHODS



METHODS
Institutional practice. patient population:Six members of an Iranian family with CFEOM underwent complete ocular examinations including assessment of ocular motility, visual acuity, slit-lamp biomicroscopy, tonometry, and ophthalmoscopy.


METHODS
Mutation analysis of the PHOX2A gene was performed using polymerase chain reaction amplification of the coding exons and direct sequencing of polymerase chain reaction products.


METHODS
Presence or absence of mutation in PHOX2A gene in two siblings with exotropia and recessive CFEOM. Exotropia and ptosis were corrected surgically in one of the two siblings.


RESULTS
The two affected siblings had bilateral ptosis and exotropia and severe limitation of all extraocular movements. One patient underwent strabismus surgery and ptosis repair. PHOX2A mutation analysis revealed a novel nonsense mutation in exon 2 (439C-->T). Both parents and the unaffected siblings were heterozygous,and the two affected siblings were homozygous for this mutation.


CONCLUSIONS
The 439C-->T mutation in this family changes a glutamine to a stop codon (Q90X) at the beginning of the PHOX2A homeodomain region. This is the fourth CFEOM2 mutation in PHOX2A and the first nonsense mutation to be identified. It confirms PHOX2A as the autosomal recessive CFEOM2 disease gene and provides evidence that the phenotypic differences between PHOX2A mutations in man and mouse do not result from hypomorphic PHOX2A alleles in humans.
Department of Pediatric Ophthalmology and Strabismus and the Center for Genetic Eye Diseases, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Ahmad
A
Yazdani
Daniel C
DC
Chung
Mohammad R
MR
Abbaszadegan
Kholoud
K
Al-Khayer
Wai Man
WM
Chan
Milad
M
Yazdani
Kazem
K
Ghodsi
Elizabeth C
EC
Engle
Elias I
EI
Traboulsi
D001763:Blepharoptosis / Q000151:congenital / Q000235:genetics* / Q000601:surgery; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005099:Exotropia / Q000151:congenital / Q000235:genetics* / Q000601:surgery; D005133:Eye Movements; D005260:Female; D005355:Fibrosis / Q000151:congenital; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007492:Iran; D008297:Male; D008365:Manometry; D009419:Nerve Tissue Proteins; D009801:Oculomotor Muscles / Q000473:pathology*; D009886:Ophthalmoplegia / Q000151:congenital / Q000235:genetics / Q000601:surgery; D009887:Ophthalmoscopy; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014792:Visual Acuity
D018389:Codon, Nonsense; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C491061:PHOX2A protein, human; C491060:Phox2a protein, mouse; D014157:Transcription Factors