DPP6 gene disruption in a family with Gilles de la Tourette syndrome

Paolo Prontera*, Valerio Napolioni, Valentina Ottaviani, Daniela Rogaia, Carmela Fusco, Bartolomeo Augello, Domenico Serino, Valentina Parisi, Laura Bernardini, Giuseppe Merla, Andrea E. Cavanna, Emilio Donti

*Corresponding author for this work

    Research output: Contribution to journalArticle

    Abstract

    Gilles de la Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and vocal tics, frequently associated with psychiatric co-morbidities. Despite the significant level of heritability, the genetic architecture of TS still remains elusive. Herein, we investigated an Italian family where an 8-year-old boy, his father, and paternal uncle have a diagnosis of TS. Array-CGH and high resolution SNP-array analyses revealed a heterozygous microdeletion of ∼135 kb at the 7q36.2 locus in the proband and his father. Fluorescent in situ hybridization and quantitative PCR (qPCR) analyses confirmed the presence of the alteration also in the paternal uncle. The deletion selectively involves the first exon of the DPP6 gene, leading to a down-regulation of its expression, as demonstrated by the reduced messenger RNA (mRNA) levels assessed by RT-qPCR. The DPP6 gene encodes for a type II membrane glycoprotein expressed predominantly in the central nervous system. To date, a de novo DPP6 exonic duplication, of uncertain significance, was reported in one patient with TS. Moreover, the DPP6 gene has been implicated in the pathogenesis of autism spectrum disorder (ASD) and, notably, in haloperidol-induced dyskinesia. This first familial case provides evidence for association between DPP6 haploinsufficiency and TS, further suggesting a plausible molecular link between TS and ASD, and might shed some light on the efficacy and tolerability profiles of antidopaminergic agents used for tic management, thus prompting further studies on a larger cohort of patients.

    Original languageEnglish
    Pages (from-to)237-242
    Number of pages6
    JournalNeurogenetics
    Volume15
    Issue number4
    Early online date17 Aug 2014
    DOIs
    Publication statusPublished - 31 Oct 2014

    Fingerprint

    Tourette Syndrome
    Tics
    Genes
    Fathers
    Haploinsufficiency
    Polymerase Chain Reaction
    Membrane Glycoproteins
    Dyskinesias
    Haloperidol
    Fluorescence In Situ Hybridization
    Single Nucleotide Polymorphism
    Psychiatry
    Exons
    Down-Regulation
    Central Nervous System
    Morbidity
    Messenger RNA

    Keywords

    • 7q microdeletion
    • attention-deficit and hyperactivity disorder
    • autism
    • DPP6 gene
    • haloperidol
    • Tourette syndrome

    Cite this

    Prontera, P., Napolioni, V., Ottaviani, V., Rogaia, D., Fusco, C., Augello, B., ... Donti, E. (2014). DPP6 gene disruption in a family with Gilles de la Tourette syndrome. Neurogenetics, 15(4), 237-242. https://doi.org/10.1007/s10048-014-0418-9
    Prontera, Paolo ; Napolioni, Valerio ; Ottaviani, Valentina ; Rogaia, Daniela ; Fusco, Carmela ; Augello, Bartolomeo ; Serino, Domenico ; Parisi, Valentina ; Bernardini, Laura ; Merla, Giuseppe ; Cavanna, Andrea E. ; Donti, Emilio. / DPP6 gene disruption in a family with Gilles de la Tourette syndrome. In: Neurogenetics. 2014 ; Vol. 15, No. 4. pp. 237-242.
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    Prontera, P, Napolioni, V, Ottaviani, V, Rogaia, D, Fusco, C, Augello, B, Serino, D, Parisi, V, Bernardini, L, Merla, G, Cavanna, AE & Donti, E 2014, 'DPP6 gene disruption in a family with Gilles de la Tourette syndrome', Neurogenetics, vol. 15, no. 4, pp. 237-242. https://doi.org/10.1007/s10048-014-0418-9

    DPP6 gene disruption in a family with Gilles de la Tourette syndrome. / Prontera, Paolo; Napolioni, Valerio; Ottaviani, Valentina; Rogaia, Daniela; Fusco, Carmela; Augello, Bartolomeo; Serino, Domenico; Parisi, Valentina; Bernardini, Laura; Merla, Giuseppe; Cavanna, Andrea E.; Donti, Emilio.

    In: Neurogenetics, Vol. 15, No. 4, 31.10.2014, p. 237-242.

    Research output: Contribution to journalArticle

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    AU - Prontera, Paolo

    AU - Napolioni, Valerio

    AU - Ottaviani, Valentina

    AU - Rogaia, Daniela

    AU - Fusco, Carmela

    AU - Augello, Bartolomeo

    AU - Serino, Domenico

    AU - Parisi, Valentina

    AU - Bernardini, Laura

    AU - Merla, Giuseppe

    AU - Cavanna, Andrea E.

    AU - Donti, Emilio

    PY - 2014/10/31

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    N2 - Gilles de la Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and vocal tics, frequently associated with psychiatric co-morbidities. Despite the significant level of heritability, the genetic architecture of TS still remains elusive. Herein, we investigated an Italian family where an 8-year-old boy, his father, and paternal uncle have a diagnosis of TS. Array-CGH and high resolution SNP-array analyses revealed a heterozygous microdeletion of ∼135 kb at the 7q36.2 locus in the proband and his father. Fluorescent in situ hybridization and quantitative PCR (qPCR) analyses confirmed the presence of the alteration also in the paternal uncle. The deletion selectively involves the first exon of the DPP6 gene, leading to a down-regulation of its expression, as demonstrated by the reduced messenger RNA (mRNA) levels assessed by RT-qPCR. The DPP6 gene encodes for a type II membrane glycoprotein expressed predominantly in the central nervous system. To date, a de novo DPP6 exonic duplication, of uncertain significance, was reported in one patient with TS. Moreover, the DPP6 gene has been implicated in the pathogenesis of autism spectrum disorder (ASD) and, notably, in haloperidol-induced dyskinesia. This first familial case provides evidence for association between DPP6 haploinsufficiency and TS, further suggesting a plausible molecular link between TS and ASD, and might shed some light on the efficacy and tolerability profiles of antidopaminergic agents used for tic management, thus prompting further studies on a larger cohort of patients.

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    Prontera P, Napolioni V, Ottaviani V, Rogaia D, Fusco C, Augello B et al. DPP6 gene disruption in a family with Gilles de la Tourette syndrome. Neurogenetics. 2014 Oct 31;15(4):237-242. https://doi.org/10.1007/s10048-014-0418-9