Of mice and men, periodic limb movements and iron: how the human genome informs the mouse genome

Jones, Leslie C.; Earley, ChristopherJ; Allen, Richard P.; Jones, Byron C.

doi:10.1111/j.1601-183x.2008.00400.x

Cited by 15 publications

(11 citation statements)

References 7 publications

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“…Much of the ongoing work on the role of iron in RLS has been conducted by Richard Allen et al at Johns Hopkins University. [63][64][65] It is now known that reduced central nervous system (CNS) iron produces RLS symptoms largely through its effects on the dopaminergic system. 64,66 Relevance of the Four Mechanisms to Other Diseases…”

Section: Restless Legs Syndrome (Rls)mentioning

confidence: 99%

Mechanisms of Sex Difference: A Historical Perspective

Seeman

2009

Journal of Women's Health

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Section: Restless Legs Syndrome (Rls)mentioning

confidence: 99%

Mechanisms of Sex Difference: A Historical Perspective

Seeman

2009

Journal of Women's Health

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“…Recall from above that Winkelmann and colleagues [14} and Steffanson and colleagues [17] identified BTBD9 as one of several candidate genes related to RLS and periodic limb movements. In their study of iron regulation in the ventral midbrain of recombinant inbred mice, Jones and colleagues [55], identified Btbd9 as candidate for the regulation of iron in this tissue. Li and colleagues then followed up to show how manipulation of this gene in mice could replicate several of the RLS-like phenotypes [20].…”

Section: 0 Conclusionmentioning

confidence: 99%

Animal models of RLS phenotypes

Allen¹,

Donelson

Jones

et al. 2017

Sleep Medicine

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Restless legs syndrome (RLS) is a complex disorder involving sensory and motor systems. The major pathophysiology of RLS is low iron concentration in the substantia nigra, containing the cell bodies of dopamine neurons that project to the striatum, an area important for modulating movement. People who have RLS often present with normal iron values outside the brain and recent studies implicate several genes involved in the syndrome. Like most complex diseases, animal models usually do not faithfully capture the full phenotypic spectrum of “disease” which is a uniquely human construct. Nonetheless, animal models have proven useful in helping to unravel the complex pathophysiology of diseases such as RLS and suggest novel treatment paradigms. For example, hypothesis-independent genome-wide association studies (GWAS) have identified several genes as increasing risk for RLS, including BTBD9. Independently, the murine homolog, Btbd9 was identified as a candidate gene for iron regulation in the midbrain in mice. The relevance of the phenotype of another of the GWAS identified genes, MEIS1, has also been explored. The role of Btbd9 in iron regulation and RLS-like behaviors has been further evaluated in mice carrying a null mutation of the gene, and in fruit flies when the BTBD9 protein is degraded. The BTBD9 and MEIS1 stories took origin from human GWAS research, supported by work in a genetic reference population of mice (forward genetics), and further verified in mice, fish flies and worms. Finally, the role of genetics is further supported by an inbred mouse strain that displays many of the phenotypic characteristics of RLS. The role of animal models of RLS phenotypes is also extended to include periodic limb movements.

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“…Restless legs syndrome and periodic limb movements are associated with low iron in the substantia nigra and related DA dysfunction. When we conducted a study of iron concentration in ventral midbrain of mice (Jones et al, 2003), we noticed a weak QTL near Btbd9 in the mouse genome and remarked on this in a subsequent article (Jones et al, 2008). DeAndrade et al (2012) were able to produce mice with mutations in Btbd9 similar to those seen in humans and observed decreased iron, sleep disturbances and abnormal movements similar to human RLS.…”

Section: Introductionmentioning

confidence: 97%

Toxicogenetics: in search of host susceptibility to environmental toxicants

Alam

Jones

2014

Front. Genet.

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Heavy metals, various pesticide and herbicides are implicated as risk factors for human health. Paraquat, maneb, and rotenone, carbamate, and organophosphorous insecticides are examples of toxicants for which acute and chronic exposure are associated with multiple neurological disorders including Parkinson’s disease. Nevertheless, the role of pesticide exposure in neurodegenerative diseases is not clear-cut, as there are inconsistencies in both the epidemiological and preclinical research. The aim of this short review is to show that at least, some of the inconsistencies are related to individual differences in susceptibility to the effects of neurotoxicants, individual differences that can be traced to the genetic constitution of the individuals and animals studies, i.e., host-based susceptibility.

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Of mice and men, periodic limb movements and iron: how the human genome informs the mouse genome

Cited by 15 publications

References 7 publications

Mechanisms of Sex Difference: A Historical Perspective

Mechanisms of Sex Difference: A Historical Perspective

Animal models of RLS phenotypes

Toxicogenetics: in search of host susceptibility to environmental toxicants

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