eprintid: 10059125 rev_number: 33 eprint_status: archive userid: 608 dir: disk0/10/05/91/25 datestamp: 2018-10-22 16:46:49 lastmod: 2021-12-24 23:22:45 status_changed: 2018-10-22 16:51:55 type: article metadata_visibility: show creators_name: Zaharieva, IT creators_name: Sarkozy, A creators_name: Munot, P creators_name: Manzur, A creators_name: O'Grady, G creators_name: Rendu, J creators_name: Malfatti, E creators_name: Amthor, H creators_name: Servais, L creators_name: Urtizberea, JA creators_name: Neto, OA creators_name: Zanoteli, E creators_name: Donkervoort, S creators_name: Taylor, J creators_name: Dixon, J creators_name: Poke, G creators_name: Foley, AR creators_name: Holmes, C creators_name: Williams, G creators_name: Holder, M creators_name: Yum, S creators_name: Medne, L creators_name: Quijano-Roy, S creators_name: Romero, NB creators_name: Fauré, J creators_name: Feng, L creators_name: Bastaki, L creators_name: Davis, MR creators_name: Phadke, R creators_name: Sewry, CA creators_name: Bönnemann, CG creators_name: Jungbluth, H creators_name: Bachmann, C creators_name: Treves, S creators_name: Muntoni, F title: STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility ispublished: pub subjects: GOSH divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: D13 divisions: G26 keywords: STAC3, congenital myopathy, excitation-contraction coupling, malignant hyperthermia note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. abstract: SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction. date: 2018-12 date_type: published official_url: https://doi.org/10.1002/humu.23635 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1582109 doi: 10.1002/humu.23635 lyricists_name: Muntoni, Francesco lyricists_name: Phadke, Rahul lyricists_name: Zaharieva, Irina lyricists_id: FMUNT02 lyricists_id: RPHAD38 lyricists_id: ITZAH49 actors_name: Waragoda Vitharana, Nimal actors_id: NWARR44 actors_role: owner full_text_status: public publication: Human Mutation volume: 39 number: 12 pagerange: 1980-1994 event_location: United States issn: 1098-1004 citation: Zaharieva, IT; Sarkozy, A; Munot, P; Manzur, A; O'Grady, G; Rendu, J; Malfatti, E; ... Muntoni, F; + view all <#> Zaharieva, IT; Sarkozy, A; Munot, P; Manzur, A; O'Grady, G; Rendu, J; Malfatti, E; Amthor, H; Servais, L; Urtizberea, JA; Neto, OA; Zanoteli, E; Donkervoort, S; Taylor, J; Dixon, J; Poke, G; Foley, AR; Holmes, C; Williams, G; Holder, M; Yum, S; Medne, L; Quijano-Roy, S; Romero, NB; Fauré, J; Feng, L; Bastaki, L; Davis, MR; Phadke, R; Sewry, CA; Bönnemann, CG; Jungbluth, H; Bachmann, C; Treves, S; Muntoni, F; - view fewer <#> (2018) STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. Human Mutation , 39 (12) pp. 1980-1994. 10.1002/humu.23635 <https://doi.org/10.1002/humu.23635>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10059125/1/Muntoni_STAC3_revised_no_TrChanges.pdf