Scientist: Research Projects: Research Articles
A Rabbit Model of Familial Craniosynostosis:
Recently, great strides have been made by members of this Center
and others in mapping and identifying the genes for a number of
syndromes which consistently include craniosynostosis as part of
the phenotype. However, the pathogenic mechanisms leading to craniosynostosis
are poorly understood due, in part, to the scarcity of adequate
number of samples of human tissues with homogeneous etiologies,
and the lack of a genetic animal model with primary craniosynostosis.
Primary craniosynostosis has been observed in inbred laboratory
rabbits and wild caught nonhuman-primates. Unfortunately a continuous
supply of craniosynostotic animals from these sources is not readily
available for research. Recently, we serendipitously obtained a
single female rabbit with craniosynostosis. In a series of reports,
we have described the development of an inbred colony of New Zealand
white rabbits with primary craniosynostosis from this single affected
female. In the affected offspring from this colony, we have also
documented the phenotypic variability, breeding demographics, pedigree
analysis, karyotypes, fetal and postnatal craniofacial and neurocapsule
dysmorphology, coronal suture pathology, synostotic progression,
spatial localization of growth factors in the perisutural tissues,
intracranial pressure and volumetric changes, and postnatal somatic,
cranial vault, and cranial base growth patterns of the affected
offspring compared to wild type control New Zealand White rabbits.
The condition in this rabbit colony appears to be primary and homogeneous,
representing familial, monogenic transmission, and probably not
syndromic transmission, chromosomal abnormalities, acute metabolic
deficiency, or prenatal intrauterine insult, as seen in other animal
models. Breeding demographic results (i.e., conception rate, gestation
length, and litter size) from this colony all appear within the
normal range of variation for other New Zealand White rabbit colonies.
In addition, no significant differences have been noted in longitudinal
somatic or postcranial skeletal growth patterns between affected
and unaffected rabbits from this colony.
Pedigree analysis of the inheritance pattern of craniosynostosis
from a number of successive back- and intercrosses of affected rabbits
from this colony suggests that this condition is inherited as an
autosomal dominant mutation with fairly high penetrance and variable
expression. Phenotypic variability ranges from rabbits with normal
coronal sutures (NCS), to rabbits with delayed onset coronal suture
synostosis (DOCSS), to rabbits with early onset coronal suture synostosis
(EOCSS), to stillborn rabbits with interfrontal suture synostosis
(IFSS). The observed ratios strongly suggest that the homozygous
dominant condition is lethal in utero with subsequent resorption
of the fetuses, as evidenced by the significantly reduced term litter
sizes (about 25% reduction). Rabbits with IFSS may represent the
autosomal dominant condition.
Results from these studies demonstrate that this colony is producing
craniosynostotic, but otherwise normal, healthy rabbits and show
that the pathological findings from this rabbit model are strikingly
similar to clinical findings noted in human infants with primary
and familial craniosynostosis. Future research is in progress with
collaborators at the Center to identify the genetic mutation in
these rabbits, describe the spatial and temporal localization and
interaction of various growth factors involved in normal and abnormal
calvarial bone regulation, and the development of cytokine therapies
to prevent postoperative resynostosis in this rabbit model.
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Cleaned and dried skulls from 25 day old normal rabbit (NCS)
(left) and rabbits with delayed onset coronal suture synostosis
(DOCSS) (middle) and early onset coronal suture synostosis
(EOCSS) (right).
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Cleaned and dried skulls from newborn normal rabbit (left)
and a rabbit with interfrontal suture synostosis (IFSS)
(right).
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Author: Mark Mooney, Ph.D.
Date: April 7, 1999
Last Updated:
6/28/02
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