Frontotemporal dementia and/or amyotrophic lateral sclerosis 1
The C9ORF72 gene at 9p21.2 codes for guanine nucleotide exchange C9orf72 a component of the guanine nucleotide exchange complex, that regulates autophagy. In this complex, guanine nucleotide exchange C9orf72 and guanine nucleotide exchange protein SMCR8 (Smith-Magenis syndrome chromosomal region candidate gene 8 protein) probably constitute the catalytic subunits that promote the exchange of GDP to GTP, thereby promoting autophagosome maturation. The complex which also contains WD repeat-containing protein 41 also acts as a negative regulator of autophagy initiation and regulates mTORC1 signaling. There are two widely expressed isoforms of guanine nucleotide exchange C9orf72.
Expansion of a GGGGCC hexanucleotide that can vary from 10 to thousands of repeats in the first intron of the C9ORF72 gene. More than 30 repeats is the cause of frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (OMIM:105550, FTDALS1). This has proved to be important in understanding that motor neuron disease, frontotemporal dementia and in particular behavioural variant frontotemporal dementia (bvFTD) are linked and indeed that cortical neurons other than motor neurons can be involved in some MND. It is believed that aborted transcripts accumulate and may cause nucleolar stress and indirectly cell death. Intermediate expansion repeats (10-30) have also been associated with other neuropsychiatric disease (eg a syndrome of anxiety-depressive disorder, slowly progressive cerebellar syndrome, mild cognitive impairment, pyramidal signs, and rapid eye movement sleep behaviour disorder. However it is also suspected that the coexistence of several mutations may explain phenotype.
- ↑ Meloni M, Farris R, Solla P, Mascia MM, Marrosu F, Cannas A. C9ORF72 Intermediate Repeat Expansion in a Patient With Psychiatric Disorders and Progressive Cerebellar Ataxia. The neurologist. 2017 Nov; 22(6):245-246.(Print) (Link to article – subscription may be required.)
- ↑ Giannoccaro MP, Bartoletti-Stella A, Piras S, Pession A, De Massis P, Oppi F, Stanzani-Maserati M, Pasini E, Baiardi S, Avoni P, Parchi P, Liguori R, Capellari S. Multiple variants in families with amyotrophic lateral sclerosis and frontotemporal dementia related to C9orf72 repeat expansion: further observations on their oligogenic nature. Journal of neurology. 2017 Jul; 264(7):1426-1433.(Print-Electronic) (Link to article – subscription may be required.)
- ↑ Farhan SMK, Gendron TF, Petrucelli L, Hegele RA, Strong MJ. OPTN p.Met468Arg and ATXN2 intermediate length polyQ extension in families with C9orf72 mediated amyotrophic lateral sclerosis and frontotemporal dementia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2017 Oct.(Print-Electronic) (Link to article – subscription may be required.)