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Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
Sheffer, Ruth; Gur, Michal; Brooks, Rebecca; Salah, Somaya; Daana, Muhannad; Fraenkel, Nitay; Eisenstein, Eli; Rabie, Malcolm; Nevo, Yoram; Jalas, Chaim; Elpeleg, Orly; Edvardson, Shimon; Harel, Tamar.
Afiliação
  • Sheffer R; Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel. Ruthsh@hadassah.org.il.
  • Gur M; Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.
  • Brooks R; Pediatric Intensive Unit, Department of Pediatrics, Mount Scopus Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • Salah S; Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.
  • Daana M; Child Development Centers, Clalit and Maccabi Health Care Services, Jerusalem, Israel.
  • Fraenkel N; Department of Respiratory Rehabilitation, Alyn Hospital, Jerusalem, Israel.
  • Eisenstein E; Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • Rabie M; Institute of Child Neurology, Schneider Children's Medical Center of Israel, Tel Aviv University, Tel Aviv, Israel.
  • Nevo Y; Institute of Child Neurology, Schneider Children's Medical Center of Israel, Tel Aviv University, Tel Aviv, Israel.
  • Jalas C; Bonei Olam, Center for Rare Jewish Genetic Diseases, Brooklyn, NY, USA.
  • Elpeleg O; Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel.
  • Edvardson S; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • Harel T; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Eur J Hum Genet ; 27(9): 1419-1426, 2019 09.
Article em En | MEDLINE | ID: mdl-30976113
The ATP/GTP-Binding Protein 1 (AGTPBP1) gene (OMIM *606830) catalyzes deglutamylation of polyglutamylated proteins, and its deficiency manifests by cerebellar ataxia and peripheral neuropathy in mice and lower motor neuron-like disease in sheep. In the mutant mice, cerebellar atrophy due to Purkinje cell degeneration is observed, likely due to increased tubulin polyglutamylation in affected brain areas. We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy. Whole exome sequencing followed by segregation analysis in the families and cDNA studies revealed deleterious biallelic variants in the AGTPBP1 gene. We conclude that complete loss-of-function of AGTPBP1 in humans, just like in mice and sheep, is associated with cerebellar and motor neuron disease, reminiscent of Pontocerebellar Hypoplasia Type 1 (PCH1).
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Tubulina (Proteína) / Degenerações Espinocerebelares / Doença dos Neurônios Motores / Proteínas de Ligação ao GTP / D-Ala-D-Ala Carboxipeptidase Tipo Serina / Alelos / Mutação Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Child, preschool / Female / Humans / Infant / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Tubulina (Proteína) / Degenerações Espinocerebelares / Doença dos Neurônios Motores / Proteínas de Ligação ao GTP / D-Ala-D-Ala Carboxipeptidase Tipo Serina / Alelos / Mutação Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Child, preschool / Female / Humans / Infant / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article