Unexpectedly mild phenotype in an ataxic family with a two-base deletion in the APTX gene

Published:April 29, 2017DOI:


      • We found a novel homozygous two-base deletion in the APTX gene.
      • An aberrantly spliced mRNA was created with a cryptic splice site.
      • The aberrant mRNA retained a frameshift mutation and encoded a truncated protein.
      • Immunoblotting did not detect the truncated protein.
      • Patients with a truncation mutation can also have a later onset of ataxia.



      Early onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia 1 (AOA1) is an autosomal recessive disorder caused by mutations in the APTX gene. In contrast to the recent progress on the molecular mechanism of aprataxin in DNA repair, the genotype and phenotype correlation has not been fully established. A previous study demonstrated that patients with truncation mutations had earlier onset of disease than those with missense mutations


      Genomic DNA analysis was performed in a consanguineous family with relatively late-onset EAOH/AOA1. In addition, mRNA and protein analyses were performed.


      The proband of the family had a homozygous two-base deletion in the middle of exon 3. Reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays of mRNA revealed an aberrantly spliced mRNA with a cryptic splice site located four bases upstream of the deletion site. The newly identified mRNA retained a frameshift mutation and encoded a truncated protein. Immunoblot analysis did not detect the truncated protein in the patient's fibroblasts, possibly because it was unstable.


      Although patients with truncation mutations had an earlier onset of disease, our findings suggest that patients with a truncation mutation resulting in an undetectable protein level can also have a later onset of disease.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Date H.
        • Onodera O.
        • Tanaka H.
        • Iwabuchi K.
        • Uekawa K.
        • Igarashi S.
        • Koike R.
        • Hiroi T.
        • Yuasa T.
        • Awaya Y.
        • Sakai T.
        • Takahashi T.
        • Nagatomo H.
        • Sekijima Y.
        • Kawachi I.
        • Takiyama Y.
        • Nishizawa M.
        • Fukuhara N.
        • Saito K.
        • Sugano S.
        • Tsuji S.
        Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene.
        Nat. Genet. 2001; 29: 184-188
        • Moreira M.C.
        • Barbot C.
        • Tachi N.
        • Kozuka N.
        • Uchida E.
        • Gibson T.
        • Mendonca P.
        • Costa M.
        • Barros J.
        • Yanagisawa T.
        • Watanabe M.
        • Ikeda Y.
        • Aoki M.
        • Nagata T.
        • Coutinho P.
        • Sequeiros J.
        • Koenig M.
        The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.
        Nat. Genet. 2001; 29: 189-193
        • Hirano M.
        • Furiya Y.
        • Kariya S.
        • Nishiwaki T.
        • Ueno S.
        Loss of function mechanism in aprataxin-related early-onset ataxia.
        Biochem. Biophys. Res. Commun. 2004; 322: 380-386
        • Hirano M.
        • Furiya Y.
        • Asai H.
        • Yasui A.
        • Ueno S.
        ALADINI482S causes selective failure of nuclear protein import and hypersensitivity to oxidative stress in triple A syndrome.
        Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 2298-2303
        • Kiriyama T.
        • Hirano M.
        • Asai H.
        • Ikeda M.
        • Furiya Y.
        • Ueno S.
        Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress.
        Biochem. Biophys. Res. Commun. 2008; 374: 631-634
        • Hirano M.
        • Yamamoto A.
        • Mori T.
        • Lan L.
        • Iwamoto T.A.
        • Aoki M.
        • Shimada K.
        • Furiya Y.
        • Kariya S.
        • Asai H.
        • Yasui A.
        • Nishiwaki T.
        • Imoto K.
        • Kobayashi N.
        • Kiriyama T.
        • Nagata T.
        • Konishi N.
        • Itoyama Y.
        • Ueno S.
        DNA single-strand break repair is impaired in aprataxin-related ataxia.
        Ann. Neurol. 2007; 61: 162-174
        • Garcia-Diaz B.
        • Barca E.
        • Balreira A.
        • Lopez L.C.
        • Tadesse S.
        • Krishna S.
        • Naini A.
        • Mariotti C.
        • Castellotti B.
        • Quinzii C.M.
        Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway.
        Hum. Mol. Genet. 2015; 24: 4516-4529
        • Yokoseki A.
        • Ishihara T.
        • Koyama A.
        • Shiga A.
        • Yamada M.
        • Suzuki C.
        • Sekijima Y.
        • Maruta K.
        • Tsuchiya M.
        • Date H.
        • Sato T.
        • Tada M.
        • Ikeuchi T.
        • Tsuji S.
        • Nishizawa M.
        • Onodera O.
        Genotype-phenotype correlations in early onset ataxia with ocular motor apraxia and hypoalbuminaemia.
        Brain. 2011; 134: 1387-1399
        • Hirano M.
        • Nishiwaki T.
        • Kariya S.
        • Furiya Y.
        • Kawahara M.
        • Ueno S.
        Novel splice variants increase molecular diversity of aprataxin, the gene responsible for early-onset ataxia with ocular motor apraxia and hypoalbuminemia.
        Neurosci. Lett. 2004; 366: 120-125
        • Tsao C.Y.
        • Paulson G.
        Type 1 ataxia with oculomotor apraxia with aprataxin gene mutations in two American children.
        J. Child Neurol. 2005; 20: 619-620
        • Castellotti B.
        • Mariotti C.
        • Rimoldi M.
        • Fancellu R.
        • Plumari M.
        • Caimi S.
        • Uziel G.
        • Nardocci N.
        • Moroni I.
        • Zorzi G.
        • Pareyson D.
        • Di Bella D.
        • Di Donato S.
        • Taroni F.
        • Gellera C.
        Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients.
        Neurogenetics. 2011; 12: 193-201
        • Le Ber I.
        • Moreira M.C.
        • Rivaud-Pechoux S.
        • Chamayou C.
        • Ochsner F.
        • Kuntzer T.
        • Tardieu M.
        • Said G.
        • Habert M.O.
        • Demarquay G.
        • Tannier C.
        • Beis J.M.
        • Brice A.
        • Koenig M.
        • Durr A.
        Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies.
        Brain. 2003; 126: 2761-2772
        • Shimazaki H.
        • Takiyama Y.
        • Sakoe K.
        • Ikeguchi K.
        • Niijima K.
        • Kaneko J.
        • Namekawa M.
        • Ogawa T.
        • Date H.
        • Tsuji S.
        • Nakano I.
        • Nishizawa M.
        Early-onset ataxia with ocular motor apraxia and hypoalbuminemia: the aprataxin gene mutations.
        Neurology. 2002; 59: 590-595
        • Hirano M.
        • Asai H.
        • Kiriyama T.
        • Furiya Y.
        • Iwamoto T.
        • Nishiwaki T.
        • Yamamoto A.
        • Mori T.
        • Ueno S.
        Short half-lives of ataxia-associated aprataxin proteins in neuronal cells.
        Neurosci. Lett. 2007; 419: 184-187
        • Ahel I.
        • Rass U.
        • El-Khamisy S.F.
        • Katyal S.
        • Clements P.M.
        • McKinnon P.J.
        • Caldecott K.W.
        • West S.C.
        The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates.
        Nature. 2006; 443: 713-716