Mouse Genome Informatics
ht
    Chd7Gt(S20-7E1)Sor/Chd7+
either: (involves: 129S4/SvJae * C57BL/6J) or (involves: 129S1/SvImJ * 129S4/SvJae C57BL/6J)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
hearing/vestibular/ear
• at 3 weeks to 11 months, heterozygotes exhibit variable asymmetric defects in posterior and lateral semicircular canals
• in contrast, the anterior semicircular canal and corresponding ampulla and crista remain normal in all heterozygotes
• notably, the utricle and saccule are present in all heterozygous ears, with no differences in shape, hair cell morphology, macular innervation or otoconia relative to wild-type ears
• at 3 weeks to 11 months, 42 of 50 heterozygous ears display a short common crus
• in the remaning 8 ears (where a distinct PSCC is absent), the area of the common crus either forms a widened bony cavity which contains a patulous common epithelial lumen (6 of 8) or appears as a cavity of normal width, which is associated with a small truncated out-pouching from the superior end in place of a normal PSCC (2 of 8)
• at 3 weeks to 11 months, all heterozygotes exhibit morphological changes in the lateral canal (LSCC), ranging from a mild alteration in canal shape to total truncation; 14 of 25 heterozygotes display similar, but not identical, defects of the LSCC between ears, and 11 of 25 show different malformation of the LSCC between ears
• although the lateral ampulla is present in most heterozygous ears, 4 of 50 ears show absence of both the ampulla and corresponding cristae; of these four, the LSCC formed a complete but smaller loop in one ear, a bird-beak in another ear, and was truncated in the remaining two ears
• none of the heterozygotes are missing the lateral ampulla in both ears
• variability is noted between different heterozygotes as well as between the right and left ear of the same mouse; of the 13 mice with at least one loop malformation of the LSCC, 5 had bilateral loops, 6 had a bird-beak deformity of the contralateral canal, and 2 had a contralateral LSCC truncation
• variability in loop size is often observed between the ears of mice with bilateral loops; of 12 heterozygotes with at least one LSCC truncation, 7 had bilateral truncations, 3 had a contralateral bird-beak, and 2 had a contralateral loop
• only 2 of the 11 heterozygotes with at least one beak had bilateral beaks; the site and extent of narrowing is variable between the ears of those mice with bilateral peaks
• the extent of LSCC truncation is also variable between ears in some mice
• intra-mouse variability is greater for the beak morphology than for the loop and truncated LSCCs
• at 3 weeks to 11 months, 19 of 50 heterozygous ears exhibit complete truncation of the non-ampullated end of the LSCC, with canal length varying from >50% of the expected circumference to no more than a tiny bud off the ampulla
• in others, LSCCs appear as complete patent loops of reduced diameter, resulting in a more circular morphology (18 of 50 ears), with significant variability noted in the diameter of the arc of the canal and of the canal lumen
• some LSCCs, display a point of luminal narrowing along their arcs which resembles a bird's beak (13 of 50 ears), most commonly found at the non-ampullated end of the canal
• this constriction is mild in some cases, but in others, the connection between the non-ampullated end and the vestibule is narrow
• at 3 weeks to 11 months, 42 of 50 heterozygotes display a complete but dysplastic posterior semicircular canal (PSCC) of a more circular "D" shape resulting from a reduced arc diameter, wider canal lumen, and a shorter common crus
• in a few ears, the superior aspect of the PSCC joins the vertical portion of the anterior semicircular canal farther along it course, resulting in an even smaller canal arc
• the size and shape of PSCC is often variable between ears of the same mouse and is bilaterally absent in only 1 of the 7 mice with absence of a distinct PSCC
• however, the posterior crista is always present within the bony posterior ampulla, regardless of whether a distinct PSCC is present
• 8 of 50 ears in 7 of 25 heterozygotes lack a distinct PSCC; only one of these 7 mice shows bilateral absence of the PSCC
• although the lateral ampulla is present in most heterozygous ears, 4 of 50 ears show absence of both the ampulla and corresponding cristae
• when present, lateral cristae show normal shape, surface morphology and neurofilament staining pattern relative to wild-type cristae; however, the width of lateral cristae is smaller in some ears
• in contrast, all anterior cristae display a normal surface morphology and innervation pattern relative to wild-type cristae
• although posterior cristae are present in all 26 heterozygous ears studied, they show morphological and/or innervation defects
• no lateral sensory epithelium is found in the 4 heterozygous ears lacking a lateral ampulla
• posterior cristae exhibit morphological ranging from a reduction in the surface area of the saddle-shaped sensory epithelium to a flattening of the saddle into a round, patch-like epithelium in all 26 ears studied
• the posterior spetum cruciatum was normal in 3 (of 26) ears and was absent in 2 ears, both of which showed a small patch-like epithelium; the other 21 had a small area devoid of stereocilia at the edge of the sensory epithelium, resembling a rudimentary septum cruciatum, located at the center of the crista

nervous system
• at 3 weeks to 11 months, heterozygotes display defects in vestibular sensory epithelial innervation despite the presence of intact hair cells in target organs
• at 3 weeks to 11 months, the vestibular nerve bundle entering the lateral cristae is visibly smaller in some ears, independent of the degree of severity of lateral canal dysplasia

behavior/neurological
• 9 of 25 heterozygotes display rapid bi-directional circling during much of their walking hours, although they do stop to eat, rest and mate
• all 9 circling mice display severe bilateral lateral canal defects (truncation or bird-beak defects on each side)
• only 3 mice with such severe bilateral lateral canal defects do not cicle, whereas all 13 mice with the less severe loop defects in at least one ear are non-ciclers
• no cicling mouse is found to have a completely patent lateral semicircular canal
• of the 18 heterozygotes with complete bilateral posterior canals, 6 circle and 12 do not
• of the 6 heterozygotes in which one posterior canal is missing while the contralateral posterior canal is intact, 2 circle and 4 do not
• 6 of 9 circlers and 12 of 18 non-circlers have both posterior canals present
• circling behavior is stronly correlated with lateral canal morphology

Mouse Models of Human Disease
OMIM IDRef(s)
CHARGE Syndrome 214800 J:123608