PURPOSE:
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. CONCLUSION: 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.
