Mutations in the Small GTPase Gene RAB39B Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly

Maila Giannandrea, Veronica Bianchi, Maria Lidia Mignogna, Alessandra Sirri, Salvatore Carrabino, Errico D'Elia, Matteo Vecellio, Silvia Russo, Francesca Cogliati, Lidia Larizza, Hans Hilger Ropers, Andreas Tzschach, Vera Kalscheuer, Barbara Oehl-Jaschkowitz, Cindy Skinner, Charles E. Schwartz, Jozef Gecz, Hilde Van Esch, Martine Raynaud, Jamel Chelly & 3 others Arjan P.M. de Brouwer, Daniela Toniolo, Patrizia D'Adamo

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3% of the general population; at least 215 X-linked MR (XLMR) conditions have been described, and mutations have been identified in 83 different genes, encoding proteins with a variety of function, such as chromatin remodeling, synaptic function, and intracellular trafficking. The small GTPases of the RAB family, which play an essential role in intracellular vesicular trafficking, have been shown to be involved in MR. We report here the identification of mutations in the small GTPase RAB39B gene in two male patients. One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5′ splice site (c.215+1G > A) and normal splicing. Neither instance produced a protein. Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly. We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment. Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. Our results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities.

LanguageEnglish
Pages185-195
Number of pages11
JournalAmerican Journal of Human Genetics
Volume86
Issue number2
DOIs
Publication statusPublished - 12 Feb 2010
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Giannandrea, Maila ; Bianchi, Veronica ; Mignogna, Maria Lidia ; Sirri, Alessandra ; Carrabino, Salvatore ; D'Elia, Errico ; Vecellio, Matteo ; Russo, Silvia ; Cogliati, Francesca ; Larizza, Lidia ; Ropers, Hans Hilger ; Tzschach, Andreas ; Kalscheuer, Vera ; Oehl-Jaschkowitz, Barbara ; Skinner, Cindy ; Schwartz, Charles E. ; Gecz, Jozef ; Van Esch, Hilde ; Raynaud, Martine ; Chelly, Jamel ; de Brouwer, Arjan P.M. ; Toniolo, Daniela ; D'Adamo, Patrizia. / Mutations in the Small GTPase Gene RAB39B Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly. In: American Journal of Human Genetics. 2010 ; Vol. 86, No. 2. pp. 185-195.
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abstract = "Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3{\%} of the general population; at least 215 X-linked MR (XLMR) conditions have been described, and mutations have been identified in 83 different genes, encoding proteins with a variety of function, such as chromatin remodeling, synaptic function, and intracellular trafficking. The small GTPases of the RAB family, which play an essential role in intracellular vesicular trafficking, have been shown to be involved in MR. We report here the identification of mutations in the small GTPase RAB39B gene in two male patients. One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5′ splice site (c.215+1G > A) and normal splicing. Neither instance produced a protein. Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly. We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment. Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. Our results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities.",
author = "Maila Giannandrea and Veronica Bianchi and Mignogna, {Maria Lidia} and Alessandra Sirri and Salvatore Carrabino and Errico D'Elia and Matteo Vecellio and Silvia Russo and Francesca Cogliati and Lidia Larizza and Ropers, {Hans Hilger} and Andreas Tzschach and Vera Kalscheuer and Barbara Oehl-Jaschkowitz and Cindy Skinner and Schwartz, {Charles E.} and Jozef Gecz and {Van Esch}, Hilde and Martine Raynaud and Jamel Chelly and {de Brouwer}, {Arjan P.M.} and Daniela Toniolo and Patrizia D'Adamo",
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Giannandrea, M, Bianchi, V, Mignogna, ML, Sirri, A, Carrabino, S, D'Elia, E, Vecellio, M, Russo, S, Cogliati, F, Larizza, L, Ropers, HH, Tzschach, A, Kalscheuer, V, Oehl-Jaschkowitz, B, Skinner, C, Schwartz, CE, Gecz, J, Van Esch, H, Raynaud, M, Chelly, J, de Brouwer, APM, Toniolo, D & D'Adamo, P 2010, 'Mutations in the Small GTPase Gene RAB39B Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly', American Journal of Human Genetics, vol. 86, no. 2, pp. 185-195. https://doi.org/10.1016/j.ajhg.2010.01.011

Mutations in the Small GTPase Gene RAB39B Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly. / Giannandrea, Maila; Bianchi, Veronica; Mignogna, Maria Lidia; Sirri, Alessandra; Carrabino, Salvatore; D'Elia, Errico; Vecellio, Matteo; Russo, Silvia; Cogliati, Francesca; Larizza, Lidia; Ropers, Hans Hilger; Tzschach, Andreas; Kalscheuer, Vera; Oehl-Jaschkowitz, Barbara; Skinner, Cindy; Schwartz, Charles E.; Gecz, Jozef; Van Esch, Hilde; Raynaud, Martine; Chelly, Jamel; de Brouwer, Arjan P.M.; Toniolo, Daniela; D'Adamo, Patrizia.

In: American Journal of Human Genetics, Vol. 86, No. 2, 12.02.2010, p. 185-195.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations in the Small GTPase Gene RAB39B Are Responsible for X-linked Mental Retardation Associated with Autism, Epilepsy, and Macrocephaly

AU - Giannandrea, Maila

AU - Bianchi, Veronica

AU - Mignogna, Maria Lidia

AU - Sirri, Alessandra

AU - Carrabino, Salvatore

AU - D'Elia, Errico

AU - Vecellio, Matteo

AU - Russo, Silvia

AU - Cogliati, Francesca

AU - Larizza, Lidia

AU - Ropers, Hans Hilger

AU - Tzschach, Andreas

AU - Kalscheuer, Vera

AU - Oehl-Jaschkowitz, Barbara

AU - Skinner, Cindy

AU - Schwartz, Charles E.

AU - Gecz, Jozef

AU - Van Esch, Hilde

AU - Raynaud, Martine

AU - Chelly, Jamel

AU - de Brouwer, Arjan P.M.

AU - Toniolo, Daniela

AU - D'Adamo, Patrizia

PY - 2010/2/12

Y1 - 2010/2/12

N2 - Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3% of the general population; at least 215 X-linked MR (XLMR) conditions have been described, and mutations have been identified in 83 different genes, encoding proteins with a variety of function, such as chromatin remodeling, synaptic function, and intracellular trafficking. The small GTPases of the RAB family, which play an essential role in intracellular vesicular trafficking, have been shown to be involved in MR. We report here the identification of mutations in the small GTPase RAB39B gene in two male patients. One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5′ splice site (c.215+1G > A) and normal splicing. Neither instance produced a protein. Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly. We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment. Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. Our results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities.

AB - Human Mental Retardation (MR) is a common and highly heterogeneous pediatric disorder affecting around 3% of the general population; at least 215 X-linked MR (XLMR) conditions have been described, and mutations have been identified in 83 different genes, encoding proteins with a variety of function, such as chromatin remodeling, synaptic function, and intracellular trafficking. The small GTPases of the RAB family, which play an essential role in intracellular vesicular trafficking, have been shown to be involved in MR. We report here the identification of mutations in the small GTPase RAB39B gene in two male patients. One mutation in family X (D-23) introduced a stop codon seven amino acids after the start codon (c.21C > A; p.Y7X). A second mutation, in the MRX72 family, altered the 5′ splice site (c.215+1G > A) and normal splicing. Neither instance produced a protein. Mutations segregate with the disease in the families, and in some family members intellectual disabilities were associated with autism spectrum disorder, epileptic seizures, and macrocephaly. We show that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that is localized to the Golgi compartment. Its downregulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. Our results demonstrate developmental and functional neuronal alteration as a consequence of downregulation of RAB39B and emphasize the critical role of vesicular trafficking in the development of neurons and human intellectual abilities.

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DO - 10.1016/j.ajhg.2010.01.011

M3 - Article

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EP - 195

JO - American Journal of Human Genetics

T2 - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

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