Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis

Praline, Julien; Blasco, Hélène; Vourc’h, Patrick; Rat, Valérian; Gendrot, Chantal; Camu, William; Andres, Christian R.

doi:10.1016/j.jns.2012.02.029

Cited by 24 publications

(26 citation statements)

References 28 publications

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“…Our findings of shorter survival and disease duration in an ALS mouse model with H67D HFE (SOD1/H67D) are not consistent with findings from ALS cases. In human studies when heterozygous and homozygous for H63D HFE are pooled, presence of H63D HFE does not affect survival, age of disease onset, disease duration and site of onset in ALS patients [18][19][20][21]24,25]. We have recently reported that ALS patients with homozygous for H63D HFE have increased disease duration [43].…”

Section: Discussionmentioning

confidence: 95%

“…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%. However, the impact of the HFE genotype on disease duration and survival is less established.…”

Section: Discussionmentioning

confidence: 96%

“…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]. Moreover, a meta-analysis indicates that the presence of the H63D HFE variant increases the risk of developing ALS by 4-fold [26].…”

Section: Introductionmentioning

confidence: 93%

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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: 95%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 93%

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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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“…There have been several independent replications of association in populations from the UK, Ireland, Italy, Netherlands, USA and China [41,105,123,130], but a recent study could not replicate these findings [92].…”

Section: Hfementioning

confidence: 99%

The genetics and neuropathology of amyotrophic lateral sclerosis

et al. 2012

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons leading to death from respiratory failure within about 3 years of symptom onset. A family history of ALS is obtained in about 5 % but the distinction between familial and apparently sporadic ALS is artificial and genetic factors play a role in all types. For several years, only one gene was known to have a role in ALS pathogenesis, SOD1. In the last few years there has been a rapid advance in our genetic knowledge of the causes of ALS, and the relationship of the genetic subtypes with pathological subtypes and clinical phenotype. Mutations in the gene for TDP-43 protein, TARDBP, highlight this, with pathology mimicking closely that found in other types of ALS, and a phenotypic spectrum that includes frontotemporal dementia. Mutations in the FUS gene, closely related to TDP-43, lead to a similar clinical phenotype but distinct pathology, so that the three pathological groups represented by SOD1, TARDBP, and FUS are distinct. In this review, we explore the genetic architecture of ALS, highlight some of the genes implicated in pathogenesis, and describe their phenotypic range and overlap with other diseases.

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“…The heterozygous condition (H/D) does not lead to a clinical haemochromatosis pattern but has been related, with variable results, to modifications in the transferrin saturation levels [21,22]. At the brain level, H63D homozygosis has been related to an increased risk of a number of neurodegenerative disorders, such as AD [23,24] and, with variable results, to amyotrophic lateral sclerosis [25,26,27,28]. To our knowledge, there are no data on the effect of the heterozygous condition on brain functioning.…”

Section: Introductionmentioning

confidence: 99%

Iron in Frontotemporal Lobar Degeneration: A New Subcortical Pathological Pathway?

Gazzina

Premi²,

Zanella³

et al. 2015

Neurodegener Dis

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Introduction: Brain iron homeostasis dysregulation has been widely related to neurodegeneration. In particular, human haemochromatosis protein (HFE) is involved in iron metabolism, and HFE H63D polymorphism has been related to the risk of amyotrophic lateral sclerosis and Alzheimer's disease. Recently, iron accumulation in the basal ganglia of frontotemporal lobar degeneration (FTLD) patients has been described. Objective: To explore the relationship between HFE genetic variation and demographic, clinical and imaging characteristics in a large cohort of FTLD patients. Methods: A total of 110 FTLD patients underwent neuropsychological and imaging evaluation and blood sampling for HFE polymorphism determination. HFE H63D polymorphism was considered in the present study. Two imaging approaches were applied to evaluate the effect of HFE genetic variation on brain atrophy, namely voxel-based morphometry and region of interest-based probabilistic approach (SPM8; Wellcome Trust Centre for Neuroimaging). Results: FTLD patients carrying the D* genotype (H/D or D/D) showed greater atrophy in the basal ganglia, bilaterally, compared to H/H carriers (x, y, z: -22, -4, 0; T = 3.45; cluster size: 33 voxels, x, y, z: 24, 4, -2; T = 3.38; cluster size: 36 voxels). The former group had even more pronounced behavioural symptoms, as defined by the Frontal Behavioural Inventory total scores. Conclusions: Our data suggest that H63D polymorphism could represent a disease-modifying gene in FTLD, fostering iron deposition in the basal ganglia. This suggests a new possible mechanism of FTLD-associated neurodegeneration.

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Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis

Cited by 24 publications

References 28 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

The genetics and neuropathology of amyotrophic lateral sclerosis

Iron in Frontotemporal Lobar Degeneration: A New Subcortical Pathological Pathway?

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