Dissecting the genetic susceptibility to complex human diseases is challenging, due to many constraints in humans, such as genetic heterogeneity, environmental factors, and sporadic occurrence. These constraints greatly diminish the power of modern human genetics tools to discern potential genetic link between diverse phenotypes (variability of disease severity, presentation, age of onset, etc.) to a single genetic locus. The situation is worsened when genetic alterations lie outside of the coding sequence. To overcome these constraints in human and to develop more effective strategy to enhance the resolution of discerning subtle genetic or epigenetic alterations as a mechanism for human disease susceptibility, a reverse population genetics approach, i.e., a population study in a cohort of mice with defined genetic alteration, was developed. The effectiveness of this approach was demonstrated by linking Gdnf locus to Hirschsprung disease (HSCR) susceptibility in a cohort of mice lacking one functioning Gdnf allele. The mutant cohort recapitulates characteristic features of the human disease. This novel model allows us to study the developmental mechanisms of disease pathogenesis that might be relevant to most HSCR patients. In a broader sense, our results establish a general paradigm for dissecting the genetic basis for human disease susceptibility in mice (Am. J. Human Genet.). Using the same population genetics approach, we extended the scope of phenotyping analyses to adult mice of their entire life span. Glial cell-line derived neurotrophic factor (GDNF) and its signaling pathway, GFRa1, the ligand binding receptor, and c-Ret, a receptor tyrosine kinase, play a critical role in kidney organ formation and enteric nervous system development. Homozygous mice missing any one component of signaling pathway (Gdnf-/-, Gfra1-/- or c-ret-/-) die at birth due to bilateral renal agenesis and enteric total aganglionosis. While 8-20% of Gdnf+/- mice died of Hirschsprung disease before weaning (3 weeks of age), majority of Gdnf+/- mice appear to be normal and reach to adulthood. However, detailed life-course epidemiology study on a large cohort of 5,000 mice revealed accelerated aging, defined as increased morbidity and mortality, in mice missing a functioning allele at Gdnf or Gfra1 locus or both. Except few adult mice that develop severe polycystic kidney disease before 7 months of age, or exhibit fecal retention, a sign of chronic constipation, Gdnf and Gfra1 deficient mice are at increased risk to develop or more likely to die of many common chronic diseases, such as hypertension, congestive heart failure, type II diabetes, cancer and senile dementia (manscript in preparation). Many confounding factors known to affect disease frequency, such as the genetic background, environmental factors and the parental origin of mutant alleles are excluded. The life course epidemiological study on these mice points to a common link underlying the diverse clinical manifestations in the cohort. Our previous findings on specific kidney and gastrointestinal tract defects in these homozygous mice at birth lead us to hypothesize that the increased risk for chronic diseases and accelerated aging of the cohort may be a result of impaired homeostasis, due to reduced inborn kidney organ reserve, in addition to direct effect of GDNF expression in adult organs. To provide direct experimental evidence that chronic diseases are the diseases of the system, we took a systematic and quantitative approach to trace the genotypic difference in lifespan, frequency of diseases, the age of onset, gender bias, to a subtle difference in renal filtering capacity at birth. We found that the organ reserve at birth is the most predictive of life course as adult. Detailed systematic approach revealed a stereotypic, sequential, dynamic and hierarchical system level integration that can be traced back to inborn renal capacity: The attempt of an organism to compensate for the inborn deficiency increases the risk to chronic diseases in diverse organs in a genotype and time-specific manner. The population genetics study of single gene mutations bridges the gap between longitudinal epidemiological studies in humans and the population studies in other model organisms like yeast, Drosophila and C. elegans. The dynamisms revealed by this systematic integrative approach will yield much needed insight on preclinical diagnoses, prior to clinical manifestation of diseases, and on preventative and therapeutic strategies (manscript in preparation).
| Granholm, A C; Reyland, M; Albeck, D et al. (2000) Glial cell line-derived neurotrophic factor is essential for postnatal survival of midbrain dopamine neurons. J Neurosci 20:3182-90 |
| Messer, C J; Eisch, A J; Carlezon Jr, W A et al. (2000) Role for GDNF in biochemical and behavioral adaptations to drugs of abuse. Neuron 26:247-57 |
| Oppenheim, R W; Houenou, L J; Parsadanian, A S et al. (2000) Glial cell line-derived neurotrophic factor and developing mammalian motoneurons: regulation of programmed cell death among motoneuron subtypes. J Neurosci 20:5001-11 |
