Abstract
Infantile hydrocephalus results in neurological deficits despite surgical treatment. Fetal-onset hydrocephalus in humans can be caused by developmental abnormalities that are genetic in origin. The H-Tx rat has hydrocephalus with 40% penetrance and a polygenic inheritance. A backcross with Fisher F344 inbred strain produced a total of 1500 progeny with 17.5% hydrocephalus. Of these, only 12.3% had overt disease and the remaining 5.2% had mild disease seen only after fixation of the brain. Disease severity was measured for all affected rats using the ratio of ventricle to brain width. The severity measure confirmed that there are two populations, mild hydrocephalus (M; ratio, <0.4) and severe hydrocephalus (S; ratio, >0.4), with a small overlap. For genotyping, the two populations were each subdivided based on the ratio measure to give a total of four groups of increasing severity. After an initial genome scan with microsatellite markers, all hydrocephalic rats and a subset of 128 normal progeny were genotyped on chromosomes 4, 9, 10, 11, 17 and 19. Rats in the mildest group had association with a locus on chromosome 4 (LOD 2.4), whereas those in the severest group were associated with a locus on chromosome 17 (LOD 3.2). All except the least affected group were associated with a heterozygous genotype on chromosomes 10 and 11 (LOD 4.5 and 3.5, respectively). Chromosomes 9 and 19 had weak linkage to hydrocephalus. The number of hydrocephalus-associated loci carried by each rat correlated with the severity of disease. It is concluded that the severity of hydrocephalus in H-Tx is influenced by different genetic loci.
Similar content being viewed by others
REFERENCES
Barros-Nunes, P., andRivas, F. (1993). Autosomal recessive congenital stenosis of aqueduct of Sylvius. Genet. Couns. 4: 19-23.
Borit, A., andSidman, R. L. (1972). New mutant mouse with communicating hydrocephalus and secondary aqueduct stenosis. Acta Neuropathol. Berl. 21: 316-331.
Brookshire, B. L.,Fletcher, J. M.,Bohan, T. P.,Landry, S. H.,Davidson, K. C., andFrancis, D. J. (1995). Verbal and non verbal skill discrepancies in children with hydrocephalus: A five-year longitudinal follow-up. J. Pediatr. Psychol. 20: 785-800.
Bruni, J. E.,Del Bigio, M. R.,Cardoso, E. R., andPersaud, T. V. N. (1988). Neuropathology of congenital hydrocephalus in the SUMS/NP mouse. Acta Neurochir. 92: 118-122.
D'Amato, C. J.,O'hea, K. S.,Hicks, S. P.,Glover, R. A., andAnnesley, T. M. (1986). Genetic prenatal aqueductal stenosis with hydrocephalus in rat. J. Neuropathol. Exp. Neurol. 45: 665-682.
Dennis, M.,Fitz, C. R.,Netley, C. T.,Sugar, J.,Harnwod-Nash, D. C. F.,Hendrick, B.,Hoffman, H. J., andHumphreys, R. P. (1981). The intelligence of hydrocephalic children. Arch. Neurol. 38: 607-615.
Fletcher, J. M.,Bohan, T. P.,Brandt, M. E.,Brookshire, B. L.,Beaver, S. R.,Francis, D. J.,Davidson, K. C.,Thompson, N. M., andMiner, M. E. (1992). Cerebral white matter and cognition in hydrocephalic children. Arch. Neurol. 49: 818-824.
Gruneberg, H. (1943a). Two new mutant genes in the house mouse. J. Genet. 45: 22-28.
Gruneberg, H. (1943b). Congenital hydrocephalus in the mouse, a case of spurious pleiotropism. J. Genet. 45: 1-21.
Jacob, H.,Brown, D.,Bunker, R., et al. (1995). A genetic linkage map of the laboratory rat, Rattus norvegicus. Nature Genet. 9: 63-69.
Jones, H. C. andBucknall, R. M. (1988). Inherited prenatal hydrocephalus in the H-Tx rat: A morphological study. Neuropathol. Appl. Neurobiol. 14: 263-274.
Jones, H. C.,Dack, S., andEllis, C. (1987). Morphological aspects of the development of hydrocephalus in a mouse mutant (SUMS/NP). Acta Neuropathol. Berl. 72: 268-276.
Jones, H. C.,Rivera, K. M., andHarris, N. G. (1995). Learning deficits in congenitally hydrocephalic rats and prevention by early shunt treatment. Child' Nerv. Syst. 11: 665-660.
Jones, H. C.,Lopman, B. A.,Jones, T. W.,Carter, B. J.,Depelteau, J. S., andMorel, L. (2000). The expression of inherited hydrocephalus in H-Tx rats. Child' Nerv. Syst. 16: 578-584.
Jones, H. C.,Depelteau, J. S.,Carter, B. J.,Lopman, B. A., andMorel, L. (2001). Genome-wide linkage analysis of inherited hydrocephalus in the H-Tx rat. Mammal. Genome 12: 22-26.
Kiefer, M.,Eymann, R.,von Tiling, S.,Muller, A.,Steudel, W. I., andBooz, K. H. (1998). The ependyma in chronic hydrocephalus. Child' Nerv. Syst. 14: 263-270.
Kohn, D. F.,Chinookoswong, N., andChou, S. M. (1981). A new model of congenital hydrocephalus in the rat. Acta Neuropathol. Berl. 54: 211-218.
Kume, T.,Deng, K.-Y.,Winfrey, V.,Gould, D. B.,Walter, M. A., andHogan, B. L. M. (1998). The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Cell 93: 985-996.
Lander, E. S., andKruglyak, L. (1995). Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nature Genet. 11: 241-247.
Lander, E. S.,Green, P.,Abramson, J.,Barlow, A.,Daly, M. J.,Lincoln, S. E.,Newburg, L., andAbrahamson, J. (1987). MAPMAKER: An interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics 1: 174-181.
Laurence, K. M., andCoates, S. (1962). The natural history of hydrocephalus: Detailed analysis of 182 unoperated cases. Arch. Dis. Childhood 37: 345-362.
Lorber, J. (1984). The family history of uncomplicated congenital hydrocephalus: An epidemiological study based on 270 probands. Br. Med. J. 289: 281-284.
Mahler, M.,Bristol, I. J.,Sundberg, J. P.,Churchill, G. A.,Birkenmeier, E. H.,Elson, C. O., andLeiter, E. H. (1999). Genetic analysis of susceptibility to dextran sulfate sodium-induced colitis in mice. Genomics 55: 147-156.
Miyazawa, T.,Sato, K.,Ikeda, Y.,Nakamura, N., andMatsumoto, K. (1997). A rat model of spontaneously arrested hydrocephalus. Child' Nerv. Syst. 13: 189-193.
Peres-Figares, J. M.,Jimenez, D. F.,Fernandez-Llebrez, P.,Cifuentes, M.,Riera, P.,Rodriguez, S., andRodriguez, E. M. (1998). Spontaneous congenital hydrocephalus in the mutant mouse hyh. Changes in the ventricular system and the subcommissural organ. J. Neuropathol. Exp. Neurol. 57(2): 188-202.
Remmers, E. F.,Longman, R. E.,Du, Y.,O'Hare, A.,Cannon, G. W.,Griffiths, M. M., andWilder, R. L. (1996). A genome scan localizes five non-MHC loci controlling collagen-induced arthritis in rats. Nature Genet. 14: 82-85.
Santiago, M. L.,Mary, C.,Parzy, D.,Jacquet, C.,Montagutelli, X.,Parkhouse, R. M.,Lemoine, R.,Izui, S., andReininger, L. (1998). Linkage of a major quantitative trait locus to Yaa geneinduced lupus-like nephritis in (NZW 3 C57BL/6)F1 mice Eur. J. Immunol. 28: 4257-4267.
Sasaki, S.,Goto, H.,Nagano, H.,Furuya, K.,Omata, Y.,Kanazawa, K.,Suzuki, K.,Sudo, K., andCollmann, H. (1983). Congenital hydrocephalus revealed in the inbred rat LEW/Jms. Neurosurgery 13: 548-554.
Suda, K.,Sato, K.,Takeda, N.,Miyazawa, T., andArai, H. (1994). Early ventriculoperitoneal shunt-effects on learning ability and synaptogenesis of the brain in congenitally hydrocephalic H-Tx rats. Child' Nerv. Syst. 10: 19-23.
Takeuchi, I. K.,Kimura, R.,Matsuda, M., andShoji, R. (1987). Absence of subcommissural organ in the cerebral aqueduct of congenital hydrocephalus spontaneously occurring in MT/HOK1 dr mice. Acta Neuropathol. Berl. 73: 320-322.
Takeuchi, I. K.,Kimura, R., andShoji, R. (1988). Dysplasia of subcommissural organ in congenital hydrocephalus spontaneously occurring in CWS/Idr rats. Experientia 44: 338-340.
Teuscher, C.,Butterfield, R. J.,Ma, R. Z.,Zachary, J. F.,Doerge, R. W., andBlankenhorn, E. P. (1999). Sequence polymorphisms in the chemokines Scya1 (TCA-3), Scya2 (monocyte chemoattractant protein (MCP)-1), and Scya12 (MCP-5) are candidates for eae7, a locus controlling susceptibility to monophasic remitting/ nonrelapsing experimental encephalomyelitis. J. Immunol. 163: 2262-2266.
Varadi, V.,Toth, Z.,Torok, O., andPapp, Z. (1988). Heterogeneity and recurrence risk for congenital hydrocephalus (ventriculomegaly): A prospective study. Am. J. Med. Genet. 29: 305-310.
Wada, M. (1988). Congenital hydrocephalus in HTX-rats: Incidence, pathogenesis and developmental impairment. Neurol. Med. Chir. 28: 955-964.
Weis, J. J.,McCracken, B. A.,Ma, Y.,Fairbairn, D.,Roper, R. J.,Morrison, T. B.,Weis, J. H.,Zachary, J. F.,Doerge, R. W., andTeuscher, C. (1999). Identification of quantitative trait loci governing arthritis severity and humoral responses in the murine model of Lyme disease. J. Immunol. 162: 948-956.
Zlotogora, J.,Sagi, M., andCohen, T. (1994). Familial hydrocephalus of prenatal onset, Am. J. Med. Genet. 49: 202-204.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Jones, H.C., Carter, B.J., Depelteau, J.S. et al. Chromosomal Linkage Associated with Disease Severity in the Hydrocephalic H-Tx Rat. Behav Genet 31, 101–111 (2001). https://doi.org/10.1023/A:1010266110762
Issue Date:
DOI: https://doi.org/10.1023/A:1010266110762