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Familial periventricular nodular heterotopia, epilepsy and Melnick-Needles Syndrome caused by a single FLNA mutation with combined gain-of-function and loss-of-function effects.
Parrini, Elena; Mei, Davide; Pisanti, Maria Antonietta; Catarzi, Serena; Pucatti, Daniela; Bianchini, Claudia; Mascalchi, Mario; Bertini, Enrico; Morrone, Amelia; Cavaliere, Maria Luigia; Guerrini, Renzo.
Afiliação
  • Parrini E; Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital-University of Florence, Florence, Italy.
  • Mei D; Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital-University of Florence, Florence, Italy.
  • Pisanti MA; Medical Genetic Unit, AORN Cardarelli, Naples, Italy.
  • Catarzi S; Molecular and Cell Biology Laboratory, Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, Florence, Italy.
  • Pucatti D; Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital-University of Florence, Florence, Italy.
  • Bianchini C; Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital-University of Florence, Florence, Italy.
  • Mascalchi M; Quantitative and Functional Neuroradiology Research Program, Meyer Children Hospital and Careggi General Hospital, Florence, Italy.
  • Bertini E; Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Research Hospital, Rome, Italy.
  • Morrone A; Molecular and Cell Biology Laboratory, Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, Florence, Italy Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Florence, Italy.
  • Cavaliere ML; Medical Genetic Unit, AORN Cardarelli, Naples, Italy.
  • Guerrini R; Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital-University of Florence, Florence, Italy.
J Med Genet ; 52(6): 405-12, 2015 Jun.
Article em En | MEDLINE | ID: mdl-25755106
BACKGROUND: Loss-of-function mutations of the FLNA gene cause a neuronal migration disorder defined as X-linked periventricular nodular heterotopia (PNH); gain-of-function mutations are associated with a group of X-linked skeletal dysplasias designed as otopalatodigital (OPD) spectrum. We describe a family in which a woman and her three daughters exhibited a complex phenotype combining PNH, epilepsy and Melnick-Needles syndrome (MNS), a skeletal disorder assigned to the OPD spectrum. All four individuals harboured a novel non-conservative missense mutation in FLNA exon 3. METHODS: In all affected family members, we performed mutation analysis of the FLNA gene, RT-PCR, ultradeep sequencing analysis in FLNA cDNAs and western blot in lymphocyte cells to further characterise the mutation. We also assessed the effects on RT-PCR products of treatment of patients' lymphocytes with cycloheximide, a nonsense mediated mRNA decay (NMD) inhibitor. RESULTS: We identified a novel c.622G>C change in FLNA exon 3, leading to the substitution of a highly conserved aminoacid (p.Gly208Arg). Gel electrophoresis and ultradeep sequencing revealed the missense mutation as well as retention of intron 3. Cycloheximide treatment demonstrated that the aberrant mRNA transcript-retaining intron 3 is subjected to NMD. Western blot analysis confirmed reduced FLNA levels in lymphocyte cells. CONCLUSIONS: The novel c.622G>C substitution leads to two aberrant FLNA transcripts, one of which carries the missense mutation, plus a longer transcript resulting from intron 3 retention. We propose that the exceptional co-occurrence of PNH and MNS, two otherwise mutually exclusive allelic phenotypes, is the consequence of a single mutational event resulting in co-occurring gain-of-function and loss-of-function effects.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Osteocondrodisplasias / Epilepsia / Heterotopia Nodular Periventricular / Estudos de Associação Genética / Filaminas / Mutação Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Osteocondrodisplasias / Epilepsia / Heterotopia Nodular Periventricular / Estudos de Associação Genética / Filaminas / Mutação Idioma: En Ano de publicação: 2015 Tipo de documento: Article