Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice.
Mice heterozygous for the Otx2 mutation display a craniofacial malformation, known as otocephaly or agnathia-holoprosencephaly complex. The severity of the phenotype is dependent on the genetic background of a C57BL/6 (B6) strain; most of the offspring of Otx2 knock-out chimeras, which are equivalent to the F(1) of CBA and B6 strains, backcrossed with B6 females display reduction or loss of mandible, whereas those backcrossed with CBA females do not show noticeable phenotype at birth. The availability of phenotypically disparate strains renders identification of Otx2 modifier loci possible. In this study, a backcross of chimera with B6 was generated and genome-wide scans were conducted with polymorphic markers for non-mendelian distribution of alleles in Otx2 heterozygous mutant mice displaying abnormalities in the lower jaw. We identified one significant locus, Otmf18, between D18Mit68 and D18Mit120 on chromosomes 18, linked to the mandibular phenotype (LOD score 3.33). A similar replication experiment using a second backcross (N3) mouse demonstrated the presence of another significant locus, Otmf2 between D2Mit164 and D2Mit282 on chromosome 2, linked to the mandibular phenotype (LOD score 3.93). These two modifiers account for the distribution of the craniofacial malformations by the genetic effect between B6 and CBA strains. Moreover, Otmf2 contain a candidate gene for several diseases in mice and humans. These genetic studies involving an otocephalic mouse model appear to provide new insights into mechanistic pathways of craniofacial development. Furthermore, these experiments offer a powerful approach with respect to identification and characterization of candidate genes that may contribute to human agnathia-holoprosencephaly complex diseases.
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Takuichiro
T
Present address: Vertebrate Body Plan Group, RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minami Cho, Chuou-Ku, Kobe, Hyougo 650-0047, Japan.
Hatakeyama
Jun
J
Kimura-Yoshida
Chiharu
C
Tian
E
E
Takeda
Naoki
N
Ushio
Yukitaka
Y
Shiroishi
Toshihiko
T
Aizawa
Shinichi
S
Matsuo
Isao
I
D000818:Animals; D002874:Chromosome Mapping; D019465:Craniofacial Abnormalities / Q000235:genetics*; D003433:Crosses, Genetic; D004423:Ear / Q000002:abnormalities* / Q000196:embryology; D005314:Embryonic and Fetal Development; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D008334:Mandible / Q000002:abnormalities / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018895:Microsatellite Repeats; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology / Q000502:physiology*; D051857:Otx Transcription Factors; D010641:Phenotype; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D005819:Genetic Markers; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D015534:Trans-Activators