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R106C TFG variant causes infantile neuroaxonal dystrophy “plus” syndrome

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Abstract

TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile neuroaxonal dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient’s fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking.

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Acknowledgements

We are grateful to the patients and their family for their participation and contribution in this study. We also thank Dr. Giaccone for helping with the biopsy report and images.

Funding

This study received support from the Mariani Foundation of Milan.

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Authors and Affiliations

  1. Molecular Neurogenetics Unit, IRCCS Foundation, C. Besta Neurological Institute, Via L. Temolo n. 4, 20126, Milan, Italy

    A. Catania, B. Garavaglia, D. Ghezzi & V. Tiranti

  2. Department of Medicine and Surgery, PhD Programme in Molecular and Translational Medicine, Milan Bicocca University, Via Cadore 48, 20900, Monza, Italy

    A. Catania

  3. IRCCS Fondazione Stella Maris, Calambrone, Pisa, Italy

    R. Battini & R. Pasquariello

  4. Department of Experimental Medicine, University of Pisa, Pisa, Italy

    R. Battini

  5. Medical Genetics Unit, San’Orsola-Malpighi University Hospital, Via Giuseppe Massarenti 9, 40138, Bologna, Italy

    T. Pippucci

  6. Neuroradiology, Foundation IRCCS, Neurological Institute “C. Besta”, Milan, Italy

    M. L. Chiapparini

  7. Medical Genetics Unit, Sant’Orsola-Malpighi University Hospital, Department of Medical and Surgical Sciences, University of Bologna, Via Giuseppe Massarenti 9, 40138, Bologna, Italy

    M. Seri

  8. Child Neurology Unit, Foundation IRCCS, Neurological Institute C. Besta, Milan, Italy

    G. Zorzi & N. Nardocci

  9. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

    D. Ghezzi

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  1. A. Catania
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  9. N. Nardocci
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Corresponding author

Correspondence to V. Tiranti.

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The ethic board of the Scientific Institute Stella Maris (Pisa) approved the study and informed consent was obtained according to the Declaration of Helsinki from all the subjects involved.

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The authors declare that they have no conflict of interest.

Electronic supplementary materials

Supplementary Figure 1

Follow-up brain MRI of subject II-3. a–e Subject II-3. Axial (a, d) and coronal (b) FAST T2-weighted images show reduction of the supratentorial white matter, lateral ventricle enlargement, and large subarachnoid spaces as the effect of diffuse atrophy, middle cerebellar peduncle hypoplasia (star), and enlargement of the IV ventricle. Coronal image (c) shows possible hypoplasia of the optic chiasm (white arrow). e Sagittal image reveals thin corpus callosum (thin white arrow) and small brainstem. FAST imaging was required due to low patient compliance to the MRI exam. f–l Subject 2 (healthy control, matched for age) for comparison. Normal axial, coronal, and sagittal FAST T2-weighted images. (PDF 834 kb)

Supplementary Figure 2

TFG expression and assembly in patient’s fibroblasts. a Patient and controls protein samples resolved in 10% SDS/PAGE gel after incubation with anti-TFG antibody. GAPDH was used as loading control. b Densitometric analysis of WB. c Blue native gels stained for TFG protein and CO1 (Cytochrome c oxidase subunit 1) used as loading control. d Densitometric analysis of BN. Numbers of kilodaltons are given on left of gels. WB, western blot; BN, blue native (PDF 156 kb)

Supplementary Figure 3

Sub-cellular distribution of TFG in patient’s fibroblasts. Control (a, b, c) and patient (d, e, f) fixed fibroblasts after double staining with Mitotracker red (a–d), KDEL antibody (green in b–e), GM130 antibody (green in c–f), and TFG-specific antibody (green in a–d, red in b, c, e, f). To-Pro3 fluorescent dye (blue) was used for nuclear counterstaining. Original magnification of all images is × 63. Higher magnification views of the indicated regions (boxed) are also shown. The scale bars represent 30 μm (main) and 5 μm (inset). (PDF 934 kb)

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Catania, A., Battini, R., Pippucci, T. et al. R106C TFG variant causes infantile neuroaxonal dystrophy “plus” syndrome. Neurogenetics 19, 179–187 (2018). https://doi.org/10.1007/s10048-018-0552-x

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