Generation and characterization of Ccdc28b mutant mice links the Bardet-Biedl associated gene with social behavioral phenotypes

CCDC28B (coiled-coil domain-containing protein 28B) was identified as a modifier in the ciliopathy Bardet-Biedl syndrome (BBS). Our previous work in cells and zebrafish showed that CCDC28B plays a role regulating cilia length in a mechanism that is not completely understood. Here we report the generation of a Ccdc28b mutant mouse using CRISPR/Cas9 (Ccdc28b mut). After confirming the depletion of Ccdc28b ;we performed a phenotypic characterization showing that Ccdc28b mut animals present a mild phenotype: i) do not present clear structural cilia affectation, although we did observe mild defects in cilia density and cilia length in some tissues, ii) reproduce normally, and iii) do not develop retinal degeneration or obesity, two hallmark features of reported BBS murine models. In contrast, Ccdc28b mut mice did show clear social interaction defects as well as stereotypical behaviors suggestive of autism spectrum disorder (ASD). This finding is indeed relevant regarding CCDC28B as a modifier of BBS since behavioral phenotypes have been documented in BBS. Importantly however, our data suggests a possible causal link between CCDC28B and ASD-like phenotypes that exceeds the context of BBS: filtering for rare deleterious variants, we found CCDC28B mutations in eight probands from the Simmons Simplex Collection cohort. Furthermore, a phenotypic analysis showed that CCDC28B mutation carriers present lower BMI and mild communication defects compared to a randomly selected sample of SSC probands. Thus, our results suggest that mutations in CCDC28B lead to mild autism-like features in mice and humans. Overall, this work reports a novel mouse model that will be key to continue evaluating genetic interactions in BBS, deciphering the contribution of CCDC28B to modulate the presentation of BBS phenotypes. In addition, our data underscores a novel link between CCDC28B and ASD-like phenotypes, providing a novel opportunity to further our understanding of the genetic, cellular, and molecular basis of ASD.

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Characterization of behavioral phenotypes in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorder under social housing conditions using the multiple animal positioning system

Experimental Animals ◽

10.1538/expanim.18-0177 ◽

2019 ◽

Vol 68 (3) ◽

pp. 319-330 ◽

Cited By ~ 1

Author(s):

Nozomi Endo ◽

Manabu Makinodan ◽

Nami Somayama ◽

Takashi Komori ◽

Toshifumi Kishimoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Mouse Model ◽

Social Housing ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Positioning System ◽

Housing Conditions ◽

Behavioral Phenotypes

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Prospective and detailed behavioral phenotyping in DDX3X syndrome

Molecular Autism ◽

10.1186/s13229-021-00431-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lara Tang ◽

Tess Levy ◽

Sylvia Guillory ◽

Danielle Halpern ◽

Jessica Zweifach ◽

...

Keyword(s):

Genetic Disorder ◽

Autism Spectrum ◽

Phenotypic Characterization ◽

Language Delays ◽

Missense Variants ◽

Variant Genotype ◽

Diagnostic Approaches ◽

Intronic Splice Site ◽

Record Review

Abstract Background DDX3X syndrome is a recently identified genetic disorder that accounts for 1–3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored. Methods We carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions. Results Eighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype–phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants. Limitations Sample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder. Conclusion This study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype–phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes.

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Comparative Phenotypic Analysis of the Bordetella parapertussis Isolate Chosen for Genomic Sequencing

Infection and Immunity ◽

10.1128/iai.70.7.3777-3784.2002 ◽

2002 ◽

Vol 70 (7) ◽

pp. 3777-3784 ◽

Cited By ~ 35

Author(s):

Ulrich Heininger ◽

Peggy A. Cotter ◽

Howard W. Fescemyer ◽

Guillermo Martinez de Tejada ◽

Ming H. Yuk ◽

...

Keyword(s):

Phenotypic Characterization ◽

Comparative Genomic ◽

Comparative Biology ◽

Phenotypic Analysis ◽

Bordetella Parapertussis ◽

In Vivo Assays ◽

Immunocompromised Mice

ABSTRACT The genomes of three closely related bordetellae are currently being sequenced, thus providing an opportunity for comparative genomic approaches driven by an understanding of the comparative biology of these three bacteria. Although the other strains being sequenced are well studied, the strain of Bordetella parapertussis chosen for sequencing is a recent human clinical isolate (strain 12822) that has yet to be characterized in detail. This investigation reports the first phenotypic characterization of this strain, which will likely become the prototype for this species in comparison with the prototype strains of B. pertussis (Tohama I), B. bronchiseptica (RB50), and other isolates of B. parapertussis. Multiple in vitro and in vivo assays distinguished each species. B. parapertussis was more similar to B. bronchiseptica than to B. pertussis in many assays, including in BvgS signaling characteristics, presence of urease activity, regulation of urease expression by BvgAS, virulence in the respiratory tracts of immunocompromised mice, induction of anti-Bordetella antibodies, and serum antimicrobial resistance. In other assays, B. parapertussis was distinct from all other species (in pigment production) or more similar to B. pertussis (by lack of motility and cytotoxicity to a macrophage-like cell line). These results begin to provide phenotypes that can be related to genetic differences identified in the genomic sequences of bordetellae.

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Mini-mouse: phenotypic characterization of a transgenic insertional mutant allelic to pygmy

Genetics Research ◽

10.1017/s0016672300032511 ◽

1994 ◽

Vol 64 (1) ◽

pp. 27-33 ◽

Cited By ~ 23

Author(s):

Kathleen F. Benson ◽

Kiran Chada

Keyword(s):

Growth Hormone ◽

Insertional Mutagenesis ◽

Hormone Deficiency ◽

Phenotypic Characterization ◽

Spontaneous Mutant ◽

Wild Type ◽

Phenotypic Analysis ◽

Mouse Mutants ◽

Reduced Body

SummaryA phenotypic analysis was performed on two alleles at the pygmy locus which arose by insertional mutagenesis in transgenic mice. Similar to the spontaneous mutant pygmy, the adult insertional transgenic mutants are 40% of the size of wild-type litter-mates whereas adult heterozygotes are 80% of wild-type litter-mates. An analysis of the various organs revealed that, in general, there was a reduction in weight of each organ commensurate with the overall reduction in body size. However, two organs did not follow this pattern, the brain being disproportionately larger and the adrenals disproportionately smaller in the mutant mice. In addition, mini-mice have less adipose tissue than their wild-type or heterozygous litter-mates. A developmental analysis determined that mutants could first be identified on the basis of reduced body weight at day 15·5 of gestation. The small size is not due to a growth hormone deficiency so these mice differ from other known dwarf mouse mutants. Therefore they should provide insight into the growth hormone-resistant human dwarnsms and help in furthering our knowledge of mammalian growth and development.

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Prospective and detailed behavioral phenotyping in DDX3X syndrome

10.1101/2021.01.26.21250125 ◽

2021 ◽

Author(s):

Lara Tang ◽

Tess Levy ◽

Sylvia Guillory ◽

Danielle Halpern ◽

Jessica Zweifach ◽

...

Keyword(s):

Genetic Disorder ◽

Autism Spectrum ◽

Phenotypic Characterization ◽

Language Delays ◽

Missense Variants ◽

Variant Genotype ◽

Diagnostic Approaches ◽

Intronic Splice Site ◽

Record Review

ABSTRACTBackgroundDDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay (DD) and/or intellectual disability (ID) in females and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored.MethodsWe carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures; three participants in this cohort have been previously reported. We compared results against population norms and contrasted phenotypes between individuals harboring either (i) protein-truncating variants or (ii) missense variants and in-frame deletions.ResultsEighty percent of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants.LimitationsSample size is modest, however, DDX3X is a rare and underdiagnosed disorder.ConclusionThis study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions yielding a more severe phenotype.

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