C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis

Abstract

A hexanucleotide repeat expansion (HRE) in the C9orf72 gene has been identified as the most common mutation in amyotrophic lateral sclerosis (ALS) among Caucasian populations. We sought to comprehensively evaluate genetic and epigenetic variants of C9orf72 and the contribution of the HRE in Chinese ALS cases. We performed fragment-length and repeat-primed polymerase chain reaction to determine GGGGCC copy number and expansion within the C9orf72 gene in 1092 sporadic ALS (sALS) and 1062 controls from China. We performed haplotype analysis of 23 single-nucleotide polymorphisms within and surrounding C9orf72. The C9orf72 HRE was found in 3 sALS patients (0.3%) but not in control subjects (p = 0.25). For 2 of the cases with the HRE, genotypes of 8 single-nucleotide polymorphisms flanking the HRE were inconsistent with the haplotype reported to be strongly associated with ALS in Caucasian populations. For these 2 individuals, we found hypermethylation of the CpG island upstream of the repeat, an observation not detected in other sALS patients (p< 10(-8)) or controls. The detailed analysis of the C9orf72 locus in a large cohort of Chinese samples provides robust evidence that may not be consistent with a single Caucasian founder event. Both the Caucasian and Chinese haplotypes associated with HRE were highly associated with repeat lengths >8 repeats implying that both haplotypes may confer instability of repeat length.

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

“…38 Caucasian alleles frequently contain up to 43 repeats, 4 52 but in Chinese samples, >12 repeats are rarely observed. 25 The European haplotype does exist in Asian cohorts 25 27 49 but at a lower frequency (<2% in Chinese controls compared with 9% in European controls). 25 Data from the 1000-genomes project estimate the frequency of the European founder haplotype in 15% of Europeans compared with only 0.5% in Asians.…”

“…25 The European haplotype does exist in Asian cohorts 25 27 49 but at a lower frequency (<2% in Chinese controls compared with 9% in European controls). 25 Data from the 1000-genomes project estimate the frequency of the European founder haplotype in 15% of Europeans compared with only 0.5% in Asians. 49 Two Han Chinese ALS expansion carriers had methylation of the upstream CpG island but did not carry the founder haplotype, 25 implying that C9orf72 alleles may undergo dynamic mutation independent of the European haplotype.…”

“…9 Both patients in the latter study with 22 repeats exhibited cognitive and behavioural impairment similar to larger expansions and had family history of FTD, while two patients with 20 and 21 repeats had family history of dementia and psychiatric illness. In atypical PD or PD with psychosis, intermediate expansions (20)(21)(22)(23)(24)(25)(26)(27)(28)(29) were detected in three female cases with atypical parkinsonian syndromes (severe rigid akinetic parkinsonism) and neuropsychiatric symptoms including schizoaffective psychosis and an FTD-like dementia. 42 Unfortunately, these cases did not have pathological diagnosis.…”

“…16 Homozygous 56 57 ► TDP43 formation may be 'age-related' findings; pathological studies found no expansion or intermediate alleles (20)(21)(22)(23)(24)(25)(26)(27)(28)(29) repeats) among LRRK2 G2019S carriers and AD cases with concomitant TDP43-positive inclusions. 16 Variation of large-normal and intermediate C9orf72 repeat lengths by ethnicity needs to be determined ► European haplotype exists in Asian cohorts, 25 27 49 but at a lower frequency (<2% in Chinese controls compared with 9% in European controls).…”

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

“…Studies on Chinese SALS populations have yielded results indicating this sequence is not correlated to their patient populations, potentially describing a predilection for the C9orf72 hexanucleotide repeat for Caucasians. 76,77 Phylogenetic analyses suggest that the hexanucleotide first originated in Finland, with all present day GGGGCC sequences in C9orf72 owing to a single mutation event 1500 years ago and representing 46.4% of FALS and 21.1% SALS of the Finnish population. 69,78 The hexanucleotide repeat leads to the downregulation of the expression of an alternatively spliced C9orf72 transcript and to the formation of aberrant nuclear RNA foci.…”