Mutational mechanism for DAB1 (ATTTC) _n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

Abstract

Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a noncoding region of DAB1. We now investigated the mutational mechanism that originated the (ATTTC)n insertion within an ancestral (ATTTT)n. Approximately 3% of nonpathogenic (ATTTT)n alleles are interspersed by AT‐rich motifs, contrarily to mutant alleles that are composed of pure (ATTTT)n and (ATTTC)n stretches. Haplotype studies in unaffected chromosomes suggested that the primary mutational mechanism, leading to the (ATTTC)n insertion, was likely one or more T>C substitutions in an (ATTTT)n pure allele of approximately 200 repeats. Then, the (ATTTC)n expanded in size, originating a deleterious allele in DAB1 that leads to SCA37. This is likely the mutational mechanism in three similar (TTTCA)n insertions responsible for familial myoclonic epilepsy. Because (ATTTT)n tracts are frequent in the human genome, many loci could be at risk for this mutational process.

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

“…The same observation also holds for spinocerebellar ataxia 37 (SCA37, OMIM: 615945), which is caused by the same repeat expansion in the first intron of DAB1 21 . For SCA37, it has been hypothesised that the thymidine to cytosine transition occurs after expansion of the endogenous ATTTT repeat to ~200 copies followed by further expansion of the mutant ATTTC sequence 22 . The ATTTT/ATTTC strand of the repeat is aligned with the direction of gene expression in all genes reported thus far, regardless of their chromosomal orientation.…”

“…The FAME2 locus is the most frequently observed linked region for Caucasian individuals affected by this disorder whereas chromosome 8 thus far is limited to Asian individuals, therefore molecular genetic testing should take this into consideration if choosing to screen by RP-PCR. Identification of the gene and causative mutation for FAME2 opens the opportunity to explore the origins of the ATTTT/ATTTC expansion through a detailed comparison of the haplotypes and repeat structures of these individuals as has been done for SCA37 22 . There may be many additional undiagnosed individuals with a spectrum of FAME-related symptoms whose genetic causes may be due to ATTTC insertion and expansion at one of the FAME loci.…”

Investigation of the RFC1 Repeat Expansion in a Canadian and a Brazilian Ataxia Cohort: Identification of Novel Conformations

“…The presence of disease-associated or wild type repeat sequences has been observed across several expansion-associated diseases, such as SCA37 (Seixas et al, 2017; Loureiro et al, 2019), SCA10 (Matsuura et al, 2006), and FRDA (Al-Mahdawi et al, 2018). Variations interrupting the pure repeat sequences of disease-causing alleles can affect their penetrance, as well as the age at onset and severity of the conditions associated with specific repeats (Al-Mahdawi et al, 2018) Also, interruptions in the normal alleles prevent the disease-associated expansions and provide the stability of repeats in disease-causing alleles.…”

Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

“…5 The only human disease related to DAB1 is spinocerebellar ataxia type-37 (SCA37, OMIM #615945), caused by (ATTTC) n insertions in the 59UTR of DAB1. 6 Several studies show that SCA37 occurs through gain-of-function (GoF) mechanisms, of which only 1 is directly related to DAB1 expression because the insertion results in overexpression of DAB1 protein and alternative DAB1 transcripts. 7 Here, we report a patient with biallelic LoF variants in DAB1, presenting with RELN-like malformations including mild lissencephaly and cerebellar hypoplasia.…”