Severe retinopathy of prematurity associated with FZD4 mutations.
OBJECTIVE
To determine whether mutations in the FZD4 gene are a risk factor for developing severe ROP.


METHODS
Three Canadian tertiary care centers recruited premature infants prospectively and retrospectively, and assigned affectation status based on the maximum degree of severity of ROP recorded in both eyes. Mutation screening of the FZD4 gene was performed using direct sequencing. All sequence changes were evaluated for functional significance.


RESULTS
Two novel FZD4 mutations (Ala370Gly or Lys203Asn) were identified in two infants from the severe ROP group (n=71). No mutation was detected in the mild to no ROP group (n=33), and the two novel mutations were absent in 173 random Caucasian samples. Mutation Ala370Gly was also found in one sibling and one parent of the affected infant, but no signs of familial exudative vitreoretinopathy (FEVR), a condition with phenotypic overlap with ROP known to be caused by FZD4 mutations, were present in either family member.


CONCLUSIONS
Mutations in the FZD4 gene in this group of premature infants supports a role for the FZD4 pathway in the development of severe ROP and accounts for approximately 3% of severe ROP in Caucasian premature infants.
Ells
Anna
A
Calgary Retina Consultants, Calgary, Alberta, Canada.
Guernsey
Duane L
DL
Wallace
Karin
K
Zheng
Binyou
B
Vincer
Michael
M
Allen
Alexander
A
Ingram
April
A
DaSilva
Orlando
O
Siebert
Lee
L
Sheidow
Thomas
T
Beis
Jill
J
Robitaille
Johane M
JM
D000595:Amino Acid Sequence; D000818:Animals; D001724:Birth Weight; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011446:Prospective Studies; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012178:Retinopathy of Prematurity / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D017386:Sequence Homology, Amino Acid
C402930:FZD4 protein, human; D051157:Frizzled Receptors; D043562:Receptors, G-Protein-Coupled