Clinical use of frataxin measurement in a patient with a novel deletion in the FXN gene

Abstract

Friedreich ataxia (FRDA) is caused by a GAA expansion in the first intron of the FXN gene, which encodes frataxin. Four percent of patients harbor a point mutation on one allele and a GAA expansion on the other. We studied an Italian patient presenting with symptoms suggestive of FRDA, and carrying a single expanded 850 GAA allele. As a second diagnostic step, frataxin was measured in peripheral blood mononuclear cells, and proved to be in the pathological range (2.95 pg/μg total protein, 12.7 % of control levels). Subsequent sequencing revealed a novel deletion in exon 5a (c.572delC) which predicted a frameshift at codon 191 and a premature truncation of the protein at codon 194 (p.T191IfsX194). FXN/mRNA expression was reduced to 69.2 % of control levels. Clinical phenotype was atypical with absent dysarthria, and rapid disease progression. L-Buthionine-sulphoximine treatment of the proband's lymphoblasts showed a severe phenotype as compared to classic FRDA.

The alteration of the C‐terminal region of human frataxin distorts its structural dynamics and function

“…The greater destabilization observed for the truncated protein is in agreement with the atypical clinical phenotype of FXN 81-193, which exhibits a strikingly rapid disease progression [16]. In this context, we propose that a better understanding of the complex inter-relationships between protein flexibility and stability should enable the rational design and optimization of protein formulation conditions based on protein dynamics.…”

“…Taken together, these results contribute to explain why the alteration of the CTR in L198R mutant [15], or its complete truncation in FXN 81-193 [16], causes FRDA. The greater destabilization observed for the truncated protein is in agreement with the atypical clinical phenotype of FXN 81-193, which exhibits a strikingly rapid disease progression [16].…”

“…Remarkably, the finding that a frame shift produces the truncation of FXN at residue 193 ( Fig. 1) and determines FRDA with rapid disease progression [16] indicates that the CTR is crucial for the biological function of FXN. Furthermore, the CTR point mutation L198R has been found in FRDA patients [15], suggesting a key role for this stretch.…”

“…Moreover, a frame shift mutation yielding the truncated form FXN 81-193 determines FRDA with a rapid disease progression [16]. Accordingly, and based on our experience with the truncated variant FXN 90-195, which lacks the CTR [12], we hypothesized that the interaction of the CTR with the globular domain of FXN is critical for its stability and function.…”

Animal Models of Friedreich Ataxia

“…In all cases, FRDA patients have a profound but not complete frataxin deficiency, with a small residual amount of normal protein (Saccá et al, 2013;Campuzano et al, 1997). FRDA is caused by a so-far-unique mutation mechanism: the expansion of an intronic GAA triplet repeat sequence (TRS) .…”