Longer ATXN2 Coding Sequence Linked to Earlier TTR-FAP Onset in Val30Met Families, Study Shows

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by Alice Melao |

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Length of naturally occurring repeats in the sequence of the ATXN2 gene may affect the age of onset of transthyretin (TTR)-related familial amyloid polyneuropathy (FAP).

The study, “Large normal alleles of ATXN2 decrease age-at-onset in TTRFAP Val30Met patients,” was published in the journal Annals of Neurology.

Age of onset of TTR-FAP among patients who carry the most common disease-causing genetic mutation, the Val30Met — which changes valine to methionine at amino acid 30 in the transthyretin (TTR) gene — can range from age 19 to 82. In addition, early, late and even asymptomatic cases of TTR-FAP can coexist within members of a family.

This diverse TTR-FAP onset pattern highlights how little is known about the underlying mechanisms of this rare disease. To gather additional insight, Portuguese researchers evaluated the impact of additional genetic alterations in genes other than TTR.

Studies in other genetic disorders have demonstrated that naturally occurring expansion of the coding sequence of some genes could contribute to the development of unrelated diseases.

This is the case with ATXN2 gene expansion, known to cause spinocerebellar ataxia type 2 (SCA2), but it has also been identified as a major contributor to the development of amyotrophic lateral sclerosis (ALS).

With this in mind, the team analyzed a panel of 10 genes that previously had been described as having such a disease-modifying effect in 329 Portuguese patients and 70 of their non-carrier relatives, from 123 TTR-FAP Val30Met families.

The genetic analysis revealed that all tested genes — ATXN1, ATXN2, ATXN3, ATXN7, TBP, ATN1, HTT, JPH3, AR, and DMPK — had CAG repeats in their coding sequence, but in numbers to be considered non-disease-causing.

The length of the repeats in nine of the 10 genes was not found to be associated with the variability of TTR-FAP onset in the study population. But for ATXN2, the team found that patients who had one copy of the gene with more than 22 repeats had an earlier mean onset (almost six years) than patients with shorter ATXN2 versions.

In the general population, CAG repeats in this gene range from 14 to 31. In contrast, the repeats’ length was not so variable within this TTR-FAP population, ranging between 22 and 27 repeats.

Patients who had two copies of the ATXN2 gene with 22 CAG repeats had a mean age at onset of 40.92 years, whereas those with at least one longer gene copy had the disease at mean 35.63 years. Onset of the disease occurred significantly earlier in men than in women.

Supported by these findings, the team believes that CAG23-28 repeats in “ATXN2 might influence TTR aggregation and amyloid fibril formation” characteristic of TTR-FAP, “contributing as a risk factor to neurodegeneration.”

Additional studies are warranted to further explore the impact of ATXN2 gene length and the progression of TTR-FAP.