Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome.
OBJECTIVE
Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome.


METHODS
We performed direct sequence analysis of interferon regulatory factor 6 exons on samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome.


RESULTS
We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA.


CONCLUSIONS
The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. On the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect on interferon regulatory factor 6 function.
de Lima
Renata L L Ferreira
RL
Serviço de Aconselhamento Genético, UNESP, Botucatu, Sao Paulo, Brazil.
Hoper
Sarah A
SA
Ghassibe
Michella
M
Cooper
Margaret E
ME
Rorick
Nicholas K
NK
Kondo
Shinji
S
Katz
Lori
L
Marazita
Mary L
ML
Compton
John
J
Bale
Sherri
S
Hehr
Ute
U
Dixon
Michael J
MJ
Daack-Hirsch
Sandra
S
Boute
Odile
O
Bayet
Bénédicte
B
Revencu
Nicole
N
Verellen-Dumoulin
Christine
C
Vikkula
Miikka
M
Richieri-Costa
Antônio
A
Moretti-Ferreira
Danilo
D
Murray
Jeffrey C
JC
Schutte
Brian C
BC
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002971:Cleft Lip / Q000473:pathology*; D002972:Cleft Palate / Q000473:pathology*; D004252:DNA Mutational Analysis; D005091:Exons; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D038061:Lower Extremity Deformities, Congenital / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D013577:Syndrome
C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors