H63D polymorphism in the hemochromatosis gene is associated with sporadic amyotrophic lateral sclerosis in China

He, Xinqi; Lu, Xuancheng; Hu, Jing; Xi, Jing; Zhou, Dong; Shang, Huifang; Liu, L.; Zhou, Haixia; Yan, Bo; Yu, Lihua; Hu, Fayun; Liu, Z.; He, Li; Yao, Xiaoli; Xu, Yaqian

doi:10.1111/j.1468-1331.2010.03158.x

Cited by 28 publications

(29 citation statements)

References 11 publications

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“…There is increasing evidence suggesting an association between H63D HFE and ALS [18][19][20][21][22]. Even studies in which a significant increase in H63D HFE was not found in ALS patients compared to the controls [23][24][25] the percentage of ALS patients with H63D HFE is consistently reported at around 30%.…”

Section: Discussionmentioning

confidence: 89%

“…However, increasing evidence suggests an association of H63D HFE with neurodegenerative diseases including ALS [17]. Five independent groups in the United States [18], the United Kingdom [19], Italy [20], the Netherlands [21] and China [22] have reported a positive association between H63D HFE and ALS. Although three studies [23][24][25] reported no association between H63D HFE and ALS, in all studies, there is agreement that H63D HFE is present in as many as 30% of ALS patients [18][19][20][21][23][24][25].…”

Section: Introductionmentioning

confidence: 97%

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H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Nandar

Neely

Simmons

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Keywords:H63D HFE SOD1(G93A) ALS Iron Oxidative stress Gliosis H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90 days (presymptomatic), 110 days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90 days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L-ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110 days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 97%

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Nandar

Neely

Simmons

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…The model is consistent with the human population studies where H63D is a genetic modifier for ALS. The frequency of this polymorphism is as high as 30 % in sporadic ALS patients compared to 14 % in the control populations (Connor and Lee 2006;Goodall et al 2005;He et al 2011;Restagno et al 2007;Sutedja et al 2007;Wang et al 2004). The C282Y polymorphism has been linked to PD (Dekker et al 2003;Guerreiro et al 2006) and multiple sclerosis (Ristic et al 2005).…”

Section: Er Stress and Neurodegenerative Diseasementioning

confidence: 92%

Iron and ER stress in neurodegenerative disease

Liu

Connor

2012

Biometals

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Neurodegenerative disease is a condition in which subpopulations of neuronal cells of the brain and spinal cord are selectively lost. A common event in many neurodegenerative diseases is the increased level of endoplasmic reticulum (ER) stress caused by accumulation and deposits of inclusion bodies that contain abnormal aggregated proteins. However, the basis of how ER stress contributes to the selective neuronal vulnerability and degeneration remain elusive. Iron accumulation in the central nerve system is consistently present in many neurodegenerative diseases. In the past 5 years we have begun to show a relationship between polymorphisms in the HFE (high iron) gene and the risk of neurodegenerative disorders. Recent findings have suggested a connection between ER stress and iron metabolism and neurodegeneration. Here we review how the different levels of chronic ER stress contribute to the different fates of neurons, namely the adaptive response and neuronal death. And, we discuss the roles of iron and HFE genotype in selective neuronal vulnerability and degeneration through modifying the ER stress level.

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“…The first report examining the presence of HFE mutations in ALS found no association between two mutations (H63D and C282Y) and ALS patients from the USA (Yen et al, 2004). However, several subsequent studies in a total of 1133 ALS patients and almost 7000 controls individuals from the USA, Ireland, UK, Italy, The Netherlands, and China reported association between the HFE H63D polymorphism and an increased risk for ALS (Goodall et al, 2005;He et al, 2011;Restagno et al, 2007;Sutedja et al, 2007;Wang et al, 2004).…”

Section: Haemochromatosis (Hfe)mentioning

confidence: 99%

Genetics of Amyotrophic Lateral Sclerosis

Devil

Andersen

Bosch

et al. 2012

Amyotrophic Lateral Sclerosis

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H63D polymorphism in the hemochromatosis gene is associated with sporadic amyotrophic lateral sclerosis in China

Abstract: The HFE H63D polymorphism may contribute to the development of sALS in Chinese.

Cited by 28 publications

References 11 publications

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Iron and ER stress in neurodegenerative disease

Genetics of Amyotrophic Lateral Sclerosis

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