Nonsense mutations in Becker muscular dystrophy: DMD gene position and disease severity

Elenco Abstract

Domenico Gorgoglione

Nonsense mutations in Becker muscular dystrophy: DMD gene position and disease severity

Autori

DOMENICO GORGOGLIONE (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY – NEUROSCIENZE/NEUROMUSCOLARE)
DANIELE SABBATINI (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY. – )
PIETRO RIGUZZI (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY. – )
GIULIANA CAPECE (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY. – )
MARIKA PANE (THE NEMO CENTER IN ROME, FONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS, ROME, ITALY; 3DEPARTMENT OF NEUROSCIENCE, UNIVERSITÀ CATTOLICA DEL SACRO CUORE, ROME, ITALY. . – )
SERENELLA SERVIDEI (NEUROPHYSIOPATHOLOGY UNIT FONDAZIONE POLICLINICO UNIVERSITARIO A. GEMELLI IRCCS, ROME; DIPARTIMENTO UNIVERSITARIO DI NEUROSCIENZE, UNIVERSITÀ CATTOLICA DEL SACRO CUORE, ROME – )
MARTA BRIGANTI (NEUROPHYSIOPATHOLOGY UNIT FONDAZIONE POLICLINICO UNIVERSITARIO A. GEMELLI IRCCS, ROME; FONDAZIONE UILDM LAZIO ONLUS, ROME. – )
CRISTINA SANCRICCA (NEUROPHYSIOPATHOLOGY UNIT FONDAZIONE POLICLINICO UNIVERSITARIO A. GEMELLI IRCCS, ROME; FONDAZIONE UILDM LAZIO ONLUS, ROME. – )
FABIO BRUSCHI (DEPARTMENT OF PEDIATRIC NEUROSCIENCE, FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA, 20133 MILAN, ITALY. – )
ANNA ARDISSONE (DEPARTMENT OF PEDIATRIC NEUROSCIENCE, FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA, 20133 MILAN, ITALY. – )
RICCARDO MASSON (DEPARTMENT OF PEDIATRIC NEUROSCIENCE, FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA, 20133 MILAN, ITALY. – )
ANNAMARIA GALLONE (NEUROIMMUNOLOGY AND NEUROMUSCULAR DISEASES UNIT, FONDAZIONE IRCCS ISTITUTO NEUROLOGICO “CARLO BESTA”, 20133 MILAN, ITALY. – )
LORENZO MAGGI (NEUROIMMUNOLOGY AND NEUROMUSCULAR DISEASES UNIT, FONDAZIONE IRCCS ISTITUTO NEUROLOGICO “CARLO BESTA”, 20133 MILAN, ITALY. – )
ESTHER PICILLO (MEDICAL GENETICS AND CARDIOMYOLOGY, UNIVERSITY OF CAMPANIA “LUIGI VANVITELLI”, NAPOLI, ITALY. – )
ANGELA PETROSINO (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY. – )
SARA VIANELLO (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY. – )
MARTINA PENZO (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY. – )
MATTEO VILLA (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY. – )
MARIA SFRAMELI (DEPARTMENT OF CLINICAL AND EXPERIMENTAL MEDICINE, UNIVERSITY OF MESSINA, ITALY. – )
COSIMO ALLEGRI (DEPARTMENT OF CLINICAL AND EXPERIMENTAL MEDICINE, UNIVERSITY OF MESSINA, ITALY. – )
ANDREA BARP (THE NEMO CLINICAL CENTER IN MILAN, NEUROREHABILITATION UNIT, UNIVERSITY OF MILAN, ASST NIGUARDA HOSPITAL, MILAN, ITALY. – )
ALESSANDRA DI BARI (THE NEMO CLINICAL CENTER IN MILAN, NEUROREHABILITATION UNIT, UNIVERSITY OF MILAN, ASST NIGUARDA HOSPITAL, MILAN, ITALY. – )
FRANCESCA SALMIN (THE NEMO CLINICAL CENTER IN MILAN, NEUROREHABILITATION UNIT, UNIVERSITY OF MILAN, ASST NIGUARDA HOSPITAL, MILAN, ITALY. – )
EMILIO ALBAMONTE (THE NEMO CLINICAL CENTER IN MILAN, NEUROREHABILITATION UNIT, UNIVERSITY OF MILAN, ASST NIGUARDA HOSPITAL, MILAN, ITALY. – )
GIOVANNI COLACICCO (THE NEMO CLINICAL CENTER IN MILAN, NEUROREHABILITATION UNIT, UNIVERSITY OF MILAN, ASST NIGUARDA HOSPITAL, MILAN, ITALY. – )
CHIARA PANICUCCI (CENTER OF TRANSLATIONAL AND EXPERIMENTAL MYOLOGY, IRCCS ISTITUTO GIANNINA GASLINI, GENOVA, ITALY. – )
MONICA TRAVERSO (PEDIATRIC NEUROLOGY AND MUSCLE DISEASE UNIT, IRCCS ISTITUTO GIANNINA GASLINI, GENOVA, ITALY – )
CONCETTA PALERMO (THE NEMO CENTER IN ROME, FONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS, ROME, ITALY. – )
ALBERTO LERARIO (NEUROMUSCULAR AND RARE DISEASE UNIT, FONDAZIONE IRCCS CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, 20122 MILANO, ITALY. – )
DANIELE VELARDO (NEUROLOGY UNIT, FONDAZIONE IRCCS CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, 20122 MILAN, ITALY. – )
MARIA GRAZIA D’ANGELO (NEUROMUSCULAR UNIT, IRCCS EUGENIO MEDEA, BOSISIO PARINI, ITALY. – )
ANGELA BERARDINELLI (IRCCS MONDINO FOUNDATION, PAVIA, ITALY. – )
ALICE GARDANI (IRCCS MONDINO FOUNDATION, PAVIA, ITALY. – )
ROBERTA NICOTRA (IRCCS MONDINO FOUNDATION, PAVIA, ITALY; DEPARTMENT OF BRAIN AND BEHAVIORAL SCIENCES, UNIVERSITY OF PAVIA, PAVIA, ITALY. – )
STEFANO PARRAVICINI (IRCCS MONDINO FOUNDATION, PAVIA, ITALY; DEPARTMENT OF BRAIN AND BEHAVIORAL SCIENCES, UNIVERSITY OF PAVIA, PAVIA, ITALY. – )
GABRIELE SICILIANO (DEPARTMENT OF CLINICAL AND EXPERIMENTAL MEDICINE, UNIVERSITY OF PISA, PISA, ITALY. – )
GIULIA RICCI (DEPARTMENT OF CLINICAL AND EXPERIMENTAL MEDICINE, UNIVERSITY OF PISA, PISA, ITALY. – )
FRANCESCA TORRI (DEPARTMENT OF CLINICAL AND EXPERIMENTAL MEDICINE, UNIVERSITY OF PISA, PISA, ITALY. – )
GIULIO GADALETA (NEUROMUSCULAR CENTER, AOU CITTÀ DELLA SALUTE E DELLA SCIENZA, UNIVERSITY OF TORINO, TURIN, ITALY. – )
GUIDO URBANO (NEUROMUSCULAR CENTER, AOU CITTÀ DELLA SALUTE E DELLA SCIENZA, UNIVERSITY OF TORINO, TURIN, ITALY. – )
ENRICA ROLLE (NEUROMUSCULAR CENTER, AOU CITTÀ DELLA SALUTE E DELLA SCIENZA, UNIVERSITY OF TORINO, TURIN, ITALY. – )
FEDERICA RICCI (NEUROMUSCULAR CENTER, AOU CITTÀ DELLA SALUTE E DELLA SCIENZA, UNIVERSITY OF TORINO, TURIN, ITALY. – )
ADELE D’AMICO (UNIT OF MUSCULAR AND NEURODEGENERATIVE DISORDERS, BAMBINO GESU’ CHILDREN’S HOSPITAL – )
MICHELA CATTERUCCIA (UNIT OF MUSCULAR AND NEURODEGENERATIVE DISORDERS, BAMBINO GESU’ CHILDREN’S HOSPITAL – )
ANTONELLA PINI (IRCCS INSTITUTE OF THE NEUROLOGICAL SCIENCES OF BOLOGNA, NEUROMUSCULAR PEDIATRIC UNIT, BOLOGNA, ITALY. – )
MELANIA GIANNOTTA (IRCCS INSTITUTE OF THE NEUROLOGICAL SCIENCES OF BOLOGNA, NEUROMUSCULAR PEDIATRIC UNIT, BOLOGNA, ITALY. – )
ROBERTA BATTINI (DEPARTMENT OF CLINICAL AND EXPERIMENTAL MEDICINE, UNIVERSITY OF PISA, PISA, ITALY; DEPARTMENT OF DEVELOPMENTAL NEUROSCIENCE, IRCCS FONDAZIONE STELLA MARIS, PISA, ITALY. – )
GEMMA MARINELLA (DEPARTMENT OF DEVELOPMENTAL NEUROSCIENCE, IRCCS FONDAZIONE STELLA MARIS, PISA, ITALY. – )
STEFANO CARLO PREVITALI (NEUROMUSCULAR REPAIR UNIT, INSTITUTE OF EXPERIMENTAL NEUROLOGY (INSPE), DIVISION OF NEUROSCIENCE, IRCCS OSPEDALE SAN RAFFAELE, 20132 MILAN, ITALY. – )
ALBERTO ANDREA ZAMBON (NEUROMUSCULAR REPAIR UNIT, INSTITUTE OF EXPERIMENTAL NEUROLOGY (INSPE), DIVISION OF NEUROSCIENCE, IRCCS OSPEDALE SAN RAFFAELE, 20132 MILAN, ITALY. – )
ALESSANDRA FERLINI (UNIT OF MEDICAL GENETICS, DEPARTMENT OF MEDICAL SCIENCES, UNIVERSITY OF FERRARA, FERRARA, ITALY. – )
FERNANDA FORTUNATO (UNIT OF MEDICAL GENETICS, DEPARTMENT OF MEDICAL SCIENCES, UNIVERSITY OF FERRARA, FERRARA, ITALY. – )
FRANCESCA MAGRI (NEUROLOGY UNIT, FONDAZIONE IRCCS CA’ GRANDA OSPEDALE MAGGIORE POLICLINICO, 20122 MILAN, ITALY. – )
TIZIANA MONGINI (NEUROMUSCULAR CENTER, AOU CITTÀ DELLA SALUTE E DELLA SCIENZA, UNIVERSITY OF TORINO, TURIN, ITALY. – )
VALERIA ADA SANSONE (THE NEMO CLINICAL CENTER IN MILAN, NEUROREHABILITATION UNIT, UNIVERSITY OF MILAN, ASST NIGUARDA HOSPITAL, MILAN, ITALY. – )
CLAUDIO BRUNO (CENTER OF TRANSLATIONAL AND EXPERIMENTAL MYOLOGY, IRCCS ISTITUTO GIANNINA GASLINI, GENOVA, ITALY; DEPARTMENT OF NEUROSCIENCE, REHABILITATION, OPHTHALMOLOGY, GENETICS, MATERNAL AND CHILD HEALTH-DINOGMI, UNIVERSITY OF GENOVA, GENOVA, ITALY. – )
SONIA MESSINA (DEPARTMENT OF CLINICAL AND EXPERIMENTAL MEDICINE, UNIVERSITY OF MESSINA, ITALY. – )
VINCENZO NIGRO (DEPARTMENT OF CLINICAL AND EXPERIMENTAL MEDICINE, UNIVERSITY OF MESSINA, ITALY; TELETHON INSTITUTE OF GENETICS AND MEDICINE, ITALY. – )
LUISA POLITANO (MEDICAL GENETICS AND CARDIOMYOLOGY, UNIVERSITY OF CAMPANIA “LUIGI VANVITELLI”, NAPOLI, ITALY. – )
ISABELLA MORONI (DEPARTMENT OF PEDIATRIC NEUROSCIENCE, FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA, 20133 MILAN, ITALY. – )
EUGENIO MERCURI (THE NEMO CENTER IN ROME, FONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS, ROME, ITALY; DEPARTMENT OF NEUROSCIENCE, UNIVERSITÀ CATTOLICA DEL SACRO CUORE, ROME, ITALY. – )
LUCA BELLO (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY – )
ELENA PEGORARO (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY – )

Presentatore

DOMENICO GORGOGLIONE (DEPARTMENT OF NEUROSCIENCES, NEUROMUSCULAR CENTER, UNIVERSITY OF PADOVA, ITALY)

Modalità

Oral Communication

Abstract

Background: Becker muscular dystrophy (BMD) is an X-linked muscle disease, due to DMD mutations leading to quantitatively and qualitatively defective dystrophin. While nonsense mutations are usually associated with absent dystrophin expression and the more severe phenotype Duchenne muscular dystrophy, they sometimes result in BMD due to several mechanisms of dystrophin “rescue”.
Materials and Methods: From a cohort of 943 BMD patients followed by 17 Italian Neuromuscular Centers, 35 patients carrying nonsense mutations were examined for demographics, signs and symptoms at onset, loss of ambulation (LoA), left ventricular ejection fraction (LVEF), and forced vital capacity (FVC).
Results: The mean age at the last assessment was 32.47±17.65 years, with a mean age at diagnosis of 16.64±19.64 years. The incidental finding of HyperCKemia was the most frequently sign at onset, observed in 10 (43.48%) patients. Five (17.24%) patients had lost the ability to walk (median LoA. Mean LVEF% was 52.68% (52% of patients had LVEF%<55%) and FVC% 87.89% (only one patient had FVC%<50%). Twenty-two mutations, 21 single nucleotide variants (SNVs) and 1 indel mutations, were identified, all resulting in premature stop codons without frameshift. These mutations clustered at three DMD sites: the 5′ and 3′ ends of the transcript, and in-frame rod domain exons, especially 28 and 29.
Conclusions: BMD may result from nonsense mutations because of translational reinitiation (5’ cluster), in-frame exon skipping due to loss of exon recognition (rod domain), and expression of truncated dystrophin able to bind dystroglycan (3’ cluster). Their clinical spectrum recapitulates the clinical variability of BMD.