ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. There is substantial evidence suggesting that ALS is a heritable disease, and a number of genes have been identified as being causative in familial ALS. In contrast, the genetics of the much commoner sporadic form of the disease is poorly understood and no single gene has been definitively shown to increase the risk of developing ALS. In this review, we discuss the genetic evidence for each candidate gene that has been putatively associated with increased risk of sporadic ALS. We also review whole genome association studies of ALS and discuss the potential of this methodology for identifying genes relevant to motor neuron degeneration.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Aryldialkylphosphatase/genetics , Cyclic AMP Response Element-Binding Protein/genetics , DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics , Dynactin Complex , Endosomal Sorting Complexes Required for Transport , Hemochromatosis Protein , Histocompatibility Antigens Class I/genetics , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intermediate Filament Proteins/genetics , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , Microtubule-Associated Proteins/genetics , Nerve Degeneration/genetics , Nerve Tissue Proteins/genetics , Neurofilament Proteins/genetics , Peripherins , Progranulins , RNA-Binding Proteins/genetics , Ribonuclease, Pancreatic/genetics , SMN Complex Proteins , Superoxide Dismutase/genetics , Superoxide Dismutase-1 , Vascular Endothelial Growth Factor A/geneticsABSTRACT
OBJECTIVE: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD. METHODS: The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS-FTD. RESULTS: Missense changes were identified in an ALS-FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear. CONCLUSION: PGRN mutations are not a common cause of ALS phenotypes.
