Refinement of the critical 7p22.1 deletion region: Haploinsufficiency of ACTB is the cause of the 7p22.1 microdeletion-related developmental disorders

Palumbo, Orazio; Accadia, Maria; Palumbo, Pietro; Leone, Maria Pia; Scorrano, Antonio; Palladino, Teresa; Stallone, Raffaella; Bonaglia, María Clara; Carella, Massimo

doi:10.1016/j.ejmg.2017.12.008

Cited by 11 publications

(7 citation statements)

References 9 publications

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“…Loss-of-function of the ACTB gene in humans is associated with developmental delays or intellectual disability (Cuvertino et al 2017; Palumbo et al 2017). Moreover, a single-nucleotide polymorphism (SNP) of the ACTB gene that caused missense mutations was shown to be linked with several neurological phenotypes, including global developmental delay, intellectual disability, cognitive impairment, abnormal aggressive and impulsive behavior, attention deficit, hyperactivity, and autism spectrum disorders (based on DECIPHER database; http://www.decipher.sanger.ac.uk/, accessed 2018).…”

Section: Discussionmentioning

confidence: 99%

Loss of serum response factor in mature neurons in the dentate gyrus alters the morphology of dendritic spines and hippocampus-dependent behavioral tasks

et al. 2019

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Serum response factor (SRF) is a major transcription factor that regulates the expression of several plasticity-associated genes in the brain. Although the developmental expression of SRF in excitatory neurons is crucial for establishing proper hippocampal circuitry, no substantial evidence of its role in unstimulated mature neurons has been provided. The present study used time-controlled, conditional SRF knockout mice and found that the lack of SRF in adult neurons led to decreased actin levels and inactivation of the actin-severing protein cofilin 1 through its increase in phosphorylation at Ser3. The augmentation of cofilin 1 phosphorylation correlated with an alteration of dendritic spine morphology in the dentate gyrus, which was reflected by an increase in the number of spines that clustered into the long-spine category. The changes in spine morphology coincided with a lower amplitude and frequency of miniature excitatory postsynaptic currents. Moreover, SRF knockout animals were hyperactive and exhibited impairments in hippocampus-dependent behaviors, such as digging, marble burying, and nesting. Altogether, our data indicate that the adult deletion of neuronal SRF leads to alterations of spine morphology and function and hippocampus-dependent behaviors. Thus, SRF deletion in adult neurons recapitulates some aspects of morphological, electrophysiological, and behavioral changes that are observed in such psychiatric disorders as schizophrenia and autism spectrum disorders.

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Section: Discussionmentioning

confidence: 99%

Loss of serum response factor in mature neurons in the dentate gyrus alters the morphology of dendritic spines and hippocampus-dependent behavioral tasks

et al. 2019

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“…SNP array-based copy number variant (CNV) analysis was performed on genomic DNA extracted from peripheral blood lymphocytes of the patient and parents, after obtaining written informed consent, using the CytoScan HD Array (Affymetrix, Santa Clara, CA, USA) as previously described [65]. Data analysis was performed using the Chromosome Analysis Suite software version 3.1 (Affymetrix, Santa Clara, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Genomic inversions and GOLGA core duplicons underlie disease instability at the 15q25 locus

et al. 2019

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Human chromosome 15q25 is involved in several disease-associated structural rearrangements, including microdeletions and chromosomal markers with inverted duplications. Using comparative fluorescence in situ hybridization, strand-sequencing, single-molecule, real-time sequencing and Bionano optical mapping analyses, we investigated the organization of the 15q25 region in human and nonhuman primates. We found that two independent inversions occurred in this region after the fission event that gave rise to phylogenetic chromosomes XIV and XV in humans and great apes. One of these inversions is still polymorphic in the human population today and may confer differential susceptibility to 15q25 microdeletions and inverted duplications. The inversion breakpoints map within segmental duplications containing core duplicons of the GOLGA gene family and correspond to the site of an ancestral centromere, which became inactivated about 25 million years ago. The inactivation of this centromere likely released segmental duplications from recombination repression typical of centromeric regions. We hypothesize that this increased the frequency of ectopic recombination creating a hotspot of hominid inversions where dispersed GOLGA core elements now predispose this region to recurrent genomic rearrangements associated with disease.

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“…Such microdeletions of ≤2 Mb in size were identified in patients with developmental delay, intellectual disability, short stature and microcephaly (7p22.1 microdeletion syndrome); a recent compilation of 23 microdeletions had identified a common deleted region of 0.37 Mb involving the FBLX18 , ACTB , FSCN1 , RNF216 , and ZNF815P genes in such patients (Cuvertino et al, 2017). Recently, a de‐novo 60 kb microdeletion encompassing only FBXL18 and ACTB was identified in a 23‐month‐old child displaying symptoms of 7p22.1 microdeletion syndrome and distinctive facial features (Palumbo et al, 2018); (c) most recently, heterozygous variants in exons 5 and 6 of ACTB were reported in six patients with thrombocytopenia, minor facial dysmorphism, and microcephaly, with and without mild intellectual disability (Latham et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Further delineation of putative ACTB loss‐of‐function variants: A 4‐patient series

et al. 2020

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ACTB encodes β‐cytoplasmic actin, an essential component of the cytoskeleton. Based on chromosome 7p22.1 deletions that include the ACTB locus and on rare truncating ACTB variants, a phenotype resulting from ACTB haploinsufficiency was recently proposed. We report putative ACTB loss‐of‐function variants in four patients. To the best of our knowledge, we report the first 7p22.1 microdeletion confined to ACTB and the second ACTB frameshifting mutation that predicts mRNA decay. A de‐novo ACTB p.(Gly302Ala) mutation affects β‐cytoplasmic actin distribution. All four patients share a facial gestalt that is distinct from that of individuals with dominant‐negative ACTB variants in Baraitser‐Winter cerebrofrontofacial syndrome. Two of our patients had strikingly thin and sparse scalp hair. One patient had sagittal craniosynostosis and hypospadias. All three affected male children have attention deficits and mild global developmental delay. Mild intellectual disability was present in only one patient. Heterozygous ACTB deletion can allow for normal psychomotor function.

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Refinement of the critical 7p22.1 deletion region: Haploinsufficiency of ACTB is the cause of the 7p22.1 microdeletion-related developmental disorders

Cited by 11 publications

References 9 publications

Loss of serum response factor in mature neurons in the dentate gyrus alters the morphology of dendritic spines and hippocampus-dependent behavioral tasks

Loss of serum response factor in mature neurons in the dentate gyrus alters the morphology of dendritic spines and hippocampus-dependent behavioral tasks

Genomic inversions and GOLGA core duplicons underlie disease instability at the 15q25 locus

Further delineation of putative ACTB loss‐of‐function variants: A 4‐patient series

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