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Your search keyword '"Veneziano, L"' showing total 2 results
Start Over Author "Veneziano, L" Journal american journal of human genetics
2 results on '"Veneziano, L"'

1. De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions

Author

Mencacci, NE, Kamsteeg, E-J, Nakashima, K, R'Bibo, L, Lynch, DS, Balint, B, Willemsen, MAAP, Adams, ME, Wiethoff, S, Suzuki, K, Davies, CH, Ng, J, Meyer, E, Veneziano, L, Giunti, P, Hughes, D, Raymond, FL, Carecchio, M, Zorzi, G, Nardocci, N, Barzaghi, C, Garavaglia, B, Salpietro, V, Hardy, J, Pittman, AM, Houlden, H, Kurian, MA, Kimura, H, Vissers, LELM, Wood, NW, and Bhatia, KP

Subjects
Male, Protein Conformation, Molecular Sequence Data, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Mice, Young Adult, PDE10A chorea, Chorea, Report, Cyclic AMP, Genetics, Animals, Humans, Genetics(clinical), Amino Acid Sequence, Child, Cyclic GMP, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Phosphoric Diester Hydrolases, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Magnetic Resonance Imaging, Corpus Striatum, Pedigree, Mutation, Female, Sequence Alignment, Signal Transduction
Abstract

Contains fulltext : 167700.pdf (Publisher’s version ) (Open Access) Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.

Published
2016

2. Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2.

Author

Guida S, Trettel F, Pagnutti S, Mantuano E, Tottene A, Veneziano L, Fellin T, Spadaro M, Stauderman K, Williams M, Volsen S, Ophoff R, Frants R, Jodice C, Frontali M, and Pietrobon D

Subjects
Amino Acid Sequence, Calcium Channels chemistry, Calcium Channels physiology, Calcium Channels, P-Type genetics, Calcium Channels, Q-Type genetics, Cell Line, Cerebellar Ataxia classification, Chromosome Mapping, Female, Humans, Male, Membrane Potentials physiology, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Patch-Clamp Techniques, Pedigree, Protein Structure, Secondary, Protein Subunits, Transfection, Calcium Channels genetics, Cerebellar Ataxia genetics, Chromosomes, Human, Pair 19, Mutation, Missense
Abstract

Familial hemiplegic migraine, episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 are allelic disorders of the CACNA1A gene (coding for the alpha(1A) subunit of P/Q calcium channels), usually associated with different types of mutations (missense, protein truncating, and expansion, respectively). However, the finding of expansion and missense mutations in patients with EA2 has blurred this genotype-phenotype correlation. We report the first functional analysis of a new missense mutation, associated with an EA2 phenotype-that is, T-->C transition of nt 4747 in exon 28, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human alpha(1A-2) subunit, together with human beta(4) and alpha(2)delta subunits, showed that channel activity was completely abolished, although the mutated protein is expressed in the cell. These results indicate that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.

Published
2001
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