PMID- 34761259
OWN - NLM
STAT- MEDLINE
DCOM- 20220509
LR  - 20220716
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 31
IP  - 9
DP  - 2022 May 4
TI  - Clinical characterization of a novel RAB39B nonstop mutation in a family with ASD 
      and severe ID causing RAB39B downregulation and study of a Rab39b knock down 
      mouse model.
PG  - 1389-1406
LID - 10.1093/hmg/ddab320 [doi]
AB  - Autism spectrum disorder (ASD) and intellectual disability (ID) often exist 
      together in patients. The RAB39B gene has been reported to be mutated in ID 
      patients with additional clinical features ranging from ASD, macrocephaly, 
      seizures and/or early-onset parkinsonism. Here, we describe a novel RAB39B 
      nonstop mutation [Xq28; c.640 T > C; p.(*214Glnext*21)] in a family with ASD, 
      severe ID and poor motor coordination, and we assessed the pathogenicity of the 
      mutation. A heterologous cell system and a Rab39b knockdown (KD) murine model, 
      which mimic the nonstop mutation, were used to validate the deleterious effect of 
      the RAB39B mutation. The mutation led to RAB39B protein instability, resulting in 
      its increased degradation and consequent downregulation. Using a Rab39b KD mouse 
      model, we demonstrated that the downregulation of RAB39B led to increased GluA2 
      lacking Ca2+-permeable AMPAR composition at the hippocampal neuronal surface and 
      increased dendritic spine density that remained in an immature filopodia-like 
      state. These phenotypes affected behavioural performance in a disease-specific 
      manner. Rab39b KD mice revealed impaired social behaviour but intact social 
      recognition. They also showed normal anxiety-like, exploratory and motivational 
      behaviours but impaired working and associative memories. In conclusion, we found 
      a novel RAB39B nonstop variant that segregated in a family with a clinical 
      phenotype including ID, ASD and poor motor coordination. The pathogenicity of 
      mutations causing the downregulation of RAB39B proteins, impacting AMPAR 
      trafficking and dendritic spine morphogenesis, reinforced the idea that AMPAR 
      modulation and dendritic spine assets could be considered hallmarks of 
      neurodevelopmental disorders.
CI  - (c) The Author(s) 2021. Published by Oxford University Press.
FAU - Mignogna, Maria Lidia
AU  - Mignogna ML
AD  - Molecular Genetics of Intellectual Disability, Division of Neuroscience, IRCCS 
      San Raffaele Scientific Institute, 20132, Milan, Italy.
FAU - Ficarella, Romina
AU  - Ficarella R
AD  - Medical Genetics Unit, Department of Reproductive Medicine, ASL Bari, 70132, 
      Bari, Italy.
FAU - Gelmini, Susanna
AU  - Gelmini S
AD  - Molecular Genetics of Intellectual Disability, Division of Neuroscience, IRCCS 
      San Raffaele Scientific Institute, 20132, Milan, Italy.
FAU - Marzulli, Lucia
AU  - Marzulli L
AD  - Child Neuropsychiatry Unit, Department of Biomedical Sciences and Human Oncology, 
      University of Bari "Aldo Moro", 70126, Bari, Italy.
FAU - Ponzi, Emanuela
AU  - Ponzi E
AD  - Medical Genetics Unit, Department of Reproductive Medicine, ASL Bari, 70132, 
      Bari, Italy.
FAU - Gabellone, Alessandra
AU  - Gabellone A
AD  - Child Neuropsychiatry Unit, Department of Biomedical Sciences and Human Oncology, 
      University of Bari "Aldo Moro", 70126, Bari, Italy.
FAU - Peschechera, Antonia
AU  - Peschechera A
AD  - Child Neuropsychiatry Unit, Department of Biomedical Sciences and Human Oncology, 
      University of Bari "Aldo Moro", 70126, Bari, Italy.
FAU - Alessio, Massino
AU  - Alessio M
AD  - Proteome Biochemistry, Center for Omics Sciences, IRCCS San Raffaele Scientific 
      Institute, 20132, Milan, Italy.
FAU - Margari, Lucia
AU  - Margari L
AD  - Child Neuropsychiatry Unit, Department of Biomedical Sciences and Human Oncology, 
      University of Bari "Aldo Moro", 70126, Bari, Italy.
FAU - Gentile, Mattia
AU  - Gentile M
AD  - Medical Genetics Unit, Department of Reproductive Medicine, ASL Bari, 70132, 
      Bari, Italy.
FAU - D'Adamo, Patrizia
AU  - D'Adamo P
AUID- ORCID: 0000-0002-0312-5541
AD  - Molecular Genetics of Intellectual Disability, Division of Neuroscience, IRCCS 
      San Raffaele Scientific Institute, 20132, Milan, Italy.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - EC 3.6.1.- (RAB39B protein, mouse)
RN  - EC 3.6.1.- (Rab39B protein, human)
RN  - EC 3.6.5.2 (rab GTP-Binding Proteins)
SB  - IM
MH  - Animals
MH  - *Autism Spectrum Disorder/genetics
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Humans
MH  - *Intellectual Disability/genetics
MH  - Mice
MH  - Mutation
MH  - rab GTP-Binding Proteins/genetics/metabolism
PMC - PMC9071400
EDAT- 2021/11/12 06:00
MHDA- 2022/05/10 06:00
PMCR- 2021/11/11
CRDT- 2021/11/11 07:06
PHST- 2021/09/16 00:00 [received]
PHST- 2021/10/25 00:00 [revised]
PHST- 2021/10/26 00:00 [accepted]
PHST- 2021/11/12 06:00 [pubmed]
PHST- 2022/05/10 06:00 [medline]
PHST- 2021/11/11 07:06 [entrez]
PHST- 2021/11/11 00:00 [pmc-release]
AID - 6425258 [pii]
AID - ddab320 [pii]
AID - 10.1093/hmg/ddab320 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2022 May 4;31(9):1389-1406. doi: 10.1093/hmg/ddab320.