TY - JOUR
T1 - PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies
AU - Al-Amri, Ahmed H
AU - Armstrong, Paul
AU - Amici, Mascia
AU - Ligneul, Clemence
AU - Rouse, James
AU - El-Asrag, Mohammed E
AU - Pantiru, Andreea
AU - Vancollie, Valerie E
AU - Ng, Hannah W Y
AU - Ogbeta, Jennifer A
AU - Goodchild, Kirstie
AU - Ellegood, Jacob
AU - Lelliott, Christopher J
AU - Mullins, Jonathan G L
AU - Bretman, Amanda
AU - Al-Ali, Ruslan
AU - Beetz, Christian
AU - Al-Gazali, Lihadh
AU - Al Shamsi, Aisha
AU - Lerch, Jason P
AU - Mellor, Jack R
AU - Al Sayegh, Abeer
AU - Ali, Manir
AU - Inglehearn, Chris F
AU - Clapcote, Steven J
PY - 2022/8/15
Y1 - 2022/8/15
N2 - BACKGROUND: The discovery of coding variants in genes that confer risk of intellectual disability (ID) is an important step toward understanding the pathophysiology of this common developmental disability.METHODS: Homozygosity mapping, whole-exome sequencing, and cosegregation analyses were used to identify gene variants responsible for syndromic ID with autistic features in two independent consanguineous families from the Arabian Peninsula. For in vivo functional studies of the implicated gene's function in cognition, Drosophila melanogaster and mice with targeted interference of the orthologous gene were used. Behavioral, electrophysiological, and structural magnetic resonance imaging analyses were conducted for phenotypic testing.RESULTS: Homozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum-anchored lipid transfer protein, showed cosegregation with syndromic ID in both families. Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory. Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits.CONCLUSIONS: These data demonstrate the involvement of homozygous loss-of-function mutations in PDZD8 in a neurodevelopmental cognitive disorder. Model organisms with manipulation of the orthologous gene replicate aspects of the human phenotype and suggest plausible pathophysiological mechanisms centered on disrupted brain development and synaptic function. These findings are thus consistent with accruing evidence that synaptic defects are a common denominator of ID and other neurodevelopmental conditions.
AB - BACKGROUND: The discovery of coding variants in genes that confer risk of intellectual disability (ID) is an important step toward understanding the pathophysiology of this common developmental disability.METHODS: Homozygosity mapping, whole-exome sequencing, and cosegregation analyses were used to identify gene variants responsible for syndromic ID with autistic features in two independent consanguineous families from the Arabian Peninsula. For in vivo functional studies of the implicated gene's function in cognition, Drosophila melanogaster and mice with targeted interference of the orthologous gene were used. Behavioral, electrophysiological, and structural magnetic resonance imaging analyses were conducted for phenotypic testing.RESULTS: Homozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum-anchored lipid transfer protein, showed cosegregation with syndromic ID in both families. Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory. Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits.CONCLUSIONS: These data demonstrate the involvement of homozygous loss-of-function mutations in PDZD8 in a neurodevelopmental cognitive disorder. Model organisms with manipulation of the orthologous gene replicate aspects of the human phenotype and suggest plausible pathophysiological mechanisms centered on disrupted brain development and synaptic function. These findings are thus consistent with accruing evidence that synaptic defects are a common denominator of ID and other neurodevelopmental conditions.
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Animals
KW - Cognitive Dysfunction/genetics
KW - Consanguinity
KW - Drosophila
KW - Drosophila melanogaster
KW - Humans
KW - Intellectual Disability/genetics
KW - Mice
KW - Mutation/genetics
UR - https://www.biologicalpsychiatryjournal.com/article/S0006-3223(22)00019-1/fulltext
U2 - 10.1016/j.biopsych.2021.12.017
DO - 10.1016/j.biopsych.2021.12.017
M3 - Article
C2 - 35227461
SN - 0006-3223
VL - 92
SP - 323
EP - 334
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 4
ER -