title: Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing.
abstract: Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but this gene is not systematically analysed because of the absence of specific signs and difficulties in protein analysis. By using high-throughput variants screening techniques, we identified variants in TRIM32 in two patients presenting nonspecific LGMD. We report the first case of total inactivation by homozygous deletion of the entire TRIM32 gene. Of interest, the deletion removes part of the ASTN2 gene, a large gene in which TRIM32 is nested. Despite the total TRIM32 gene inactivation, the patient does not present a more severe phenotype. However, he developed a mild progressive cognitive impairment that may be related to the loss of function of ASTN2 because association between ASTN2 heterozygous deletions and neurobehavioral disorders was previously reported. Regarding genomic characteristics at breakpoint of the deleted regions of TRIM32, we found a high density of repeated elements, suggesting a possible hotspot. These observations illustrate the importance of high-throughput technologies for identifying molecular defects in LGMD, confirm that total loss of function of TRIM32 is not associated with a specific phenotype and that TRIM32/ASTN2 inactivation could be associated with cognitive impairment.
authors.affiliation: 1] Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Laboratoire de Biochimie et Génétique Moléculaire, Paris, France [2] UMR 8104, Inserm U1016, Université Paris Descartes, Institut Cochin, Laboratoire de Génétique des Maladies Neurodéveloppementales, Paris, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Nectoux
authors.affiliation: Généthon - UMR8587 LAMBE, Evry, France.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cid
authors.affiliation: Génopole Campus 2, PartnerChip, Evry, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baulande
authors.affiliation: 1] Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Laboratoire de Biochimie et Génétique Moléculaire, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 06, INSERM U974, CNRS FRE 3617, Center of Research in Myology, Institut de Myologie, Paris, France.
authors.forename: France
authors.initials: F
authors.lastname: Leturcq
authors.affiliation: Hôpital Marin, Centre de référence neuromusculaire GNMH, Hendaye, France.
authors.forename: Jon Andoni
authors.initials: JA
authors.lastname: Urtizberea
authors.affiliation: CHU Angers, Département de Neurologie, Angers, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Penisson-Besnier
authors.affiliation: CHU Angers, Département de Neurologie, Angers, France.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Nadaj-Pakleza
authors.affiliation: Généthon - UMR8587 LAMBE, Evry, France.
authors.forename: Carinne
authors.initials: C
authors.lastname: Roudaut
authors.affiliation: Génopole Campus 2, PartnerChip, Evry, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Criqui
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Laboratoire de Biochimie et Génétique Moléculaire, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Orhant
authors.affiliation: CHRU Montpellier, Laboratoire de Génétique moléculaire, Montpellier, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Peyroulan
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM U974, CNRS FRE 3617, Center of Research in Myology, Institut de Myologie, Paris, France.
authors.forename: Raba
authors.initials: R
authors.lastname: Ben Yaou
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM U974, CNRS FRE 3617, Center of Research in Myology, Institut de Myologie, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Nelson
authors.affiliation: Hôpital Marin, Centre de référence neuromusculaire GNMH, Hendaye, France.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cobo
authors.affiliation: CHU Toulouse, Centre de référence neuromusculaire, Toulouse, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Arné-Bes
authors.affiliation: CHU Toulouse, Centre de référence neuromusculaire, Toulouse, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Uro-Coste
authors.affiliation: Université Paris Descartes, Plateforme de Bioinformatique, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.affiliation: 1] CHRU Montpellier, Laboratoire de Génétique moléculaire, Montpellier, France [2] Inserm U827, Université Montpellier 1, Laboratoire de Génétique de Maladies rares, Montpellier, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.affiliation: 1] Sorbonne Universités, UPMC Univ Paris 06, INSERM U974, CNRS FRE 3617, Center of Research in Myology, Institut de Myologie, Paris, France [2] Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, France.
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.affiliation: Inserm UMR_S910, Université de la Méditerranée, Génétique médicale & Génomique Fonctionnelle, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.affiliation: 1] Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Laboratoire de Biochimie et Génétique Moléculaire, Paris, France [2] UMR 8104, Inserm U1016, Université Paris Descartes, Institut Cochin, Laboratoire de Génétique des Maladies Neurodéveloppementales, Paris, France.
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.affiliation: Généthon - UMR8587 LAMBE, Evry, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Richard
authors.affiliation: 1] CHRU Montpellier, Laboratoire de Génétique moléculaire, Montpellier, France [2] Inserm U827, Université Montpellier 1, Laboratoire de Génétique de Maladies rares, Montpellier, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Cossée
mesh_terms: D000328:Adult; D001483:Base Sequence; D055028:Comparative Genomic Hybridization / Q000379:methods*; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C094027:TRIM32 protein, human; D044767:Ubiquitin-Protein Ligases