A de novo nonsense variant and two de novo missense variants in the SPTBN1 gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the Autism Sequencing Consortium (Satterstrom et al., 2010), while rare inherited missense variants in this gene were identified in two Chinese ASD probands in Li et al., 2017. Rosenfeld et al., 2021 reported seven unrelated individuals with heterozygous SPTBN1 variants, all of whom presented with developmental delay and/or intellectual disability; three of these individuals were diagnosed with autism spectrum disorder, while autistic features were observed in a fourth. Additional de novo loss-of-function and missense variants in the SPTBN1 gene were observed in ASD probands from the MSSNG cohort and the SPARK cohort in Zhou et al., 2022. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SPTBN1 as a gene reaching exome-wide significance (P < 2.5E-06); association of SPTBN1 with ASD risk in this analysis was found to be driven predominantly by rare inherited loss-of-function variants transmitted from unaffected parents to affected offspring.
Molecular Function
Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein contains an N-terminal actin-binding domain, and 17 spectrin repeats which are involved in dimer formation.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
The conditional knockout strategy was based on the major sptbn1 transcript (id: ensmust00000006629) and a targeting construct was generated in which loxp sites were designed to flank exon 3, resulting in disruption of the reading frame uponcre-mediated excision. a genomic bac clone (bmq-431m24) containing the sptbn1 locus was purchased from geneservice ltd. cambridge park, uk. genomic dna fragments harboring exon 3 of sptbn1 were subcloned in pbluescript (stratagene). the targeting vector comprised a 6.5 kb long arm and a 1.7 kb short arm, with a pgkâ??neomycin resistance (neor) selection cassette flanked by two frt sites and the herpes simplex thymidine kinase gene. the resulting sptbn1flox/+ mice were bred to mice bearing a flp-recombinase transgene (rosa-flp) to remove the neomycin selection marker. to generate neural progenitor-specific sptbn1 null mice (sptbn1flox/flox/nestin-cre, sptbn1-ko), sptbn1flox/flox mice were crossed with the nestin-cre mouse line [b6.cg-tg(nes-cre)1kln/j, stock number 003771; the jackson laboratory].
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J * (C57BL/6 x SJL)F2
ES Cell Line: 129SV/EV
Mutant ES Cell Line: Model Source: 22632975; 31209033
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
The conditional knockout strategy was based on the major sptbn1 transcript (id: ensmust00000006629) and a targeting construct was generated in which loxp sites were designed to flank exon 3, resulting in disruption of the reading frame uponcre-mediated excision. a genomic bacterial artificial chromosome clone (bmq-431m24) containing the sptbn1 locus was purchased from geneservice ltd. cambridge park, uk. genomic dna fragments harboring exon 3 of sptbn1 were subcloned in pbluescript (stratagene). the targeting vector comprised a 6.5 kb long arm and a 1.7 kb short arm, with a pgkâ??neomycin resistance (neor) selection cassette flanked by two frt sites and the herpes simplex thymidine kinase gene. the resulting sptbn1flox/+ mice were bred to mice bearing a flp-recombinase transgene (rosa-flp) to remove the neomycin selection marker. to generate neural progenitor-specific sptbn1 haploinsuficient mice (sptbn1flox/flox/nestin-cre, sptbn1-ko), sptbn1flox/flox mice were crossed with the nestin-cre mouse line [b6.cg-tg(nes-cre)1kln/j, stock number 003771; the jackson laboratory].
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J * (C57BL/6 x SJL)F3
ES Cell Line: 129SV/EV
Mutant ES Cell Line: Model Source: 22632975; 31209033
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
The conditional knockout strategy was based on the major sptbn1 transcript (id: ensmust00000006629) and a targeting construct was generated in which loxp sites were designed to flank exon 3, resulting in disruption of the reading frame uponcre-mediated excision. a genomic bacterial artificial chromosome clone (bmq-431m24) containing the sptbn1 locus was purchased from geneservice ltd. cambridge park, uk. genomic dna fragments harboring exon 3 of sptbn1 were subcloned in pbluescript (stratagene). the targeting vector comprised a 6.5 kb long arm and a 1.7 kb short arm, with a pgkâ??neomycin resistance (neor) selection cassette flanked by two frt sites and the herpes simplex thymidine kinase gene. the resulting sptbn1flox/+ mice were bred to mice bearing a flp-recombinase transgene (rosa-flp) to remove the neomycin selection marker. mice lacking βii-spectrin in cortical projection neurons (sptbn1flox/flox/nex-cre, βii-spnexko) were generated by crossing sptbn1flox/flox and nex-cre animals for multiple generations.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J * C57Bl/6
ES Cell Line: 129SV/EV
Mutant ES Cell Line: Model Source: 22632975; 27732850; 31209033
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
The conditional knockout strategy was based on the major sptbn1 transcript (id: ensmust00000006629) and a targeting construct was generated in which loxp sites were designed to flank exon 3, resulting in disruption of the reading frame uponcre-mediated excision. a genomic bacterial artificial chromosome clone (bmq-431m24) containing the sptbn1 locus was purchased from geneservice ltd. cambridge park, uk. genomic dna fragments harboring exon 3 of sptbn1 were subcloned in pbluescript (stratagene). the targeting vector comprised a 6.5 kb long arm and a 1.7 kb short arm, with a pgkâ??neomycin resistance (neor) selection cassette flanked by two frt sites and the herpes simplex thymidine kinase gene. the resulting sptbn1flox/+ mice were bred to mice bearing a flp-recombinase transgene (rosa-flp) to remove the neomycin selection marker. mice lacking βii-spectrin in cortical projection neurons (sptbn1flox/flox/nex-cre, βii-spnexko) were generated by crossing sptbn1flox/flox and nex-cre animals for multiple generations.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J * C57Bl/6
ES Cell Line: 129SV/EV
Mutant ES Cell Line: Model Source: 22632975; 27732850; 31209033
Description: Significant increase in the diameter of myelinated axons, signs of axonal degeneration, including myelin sheath decompaction and vacuolization and dense material in the cytosol, likely reflecting breakdown of cytoskeletal elements
Description: G-ratio (ratio of diameters of inner axon and outer fiber) also increased; changes in myelin organization were predominantly found in large-diameter axons; loss of myelin was not associated with a decrease in myelin basic protein expression
Description: Reduced association of kif1a, kif5b, kif3a, and the p150glued subunit of the dynactin complex with intracellular membranes while total expression of these motors in brain postnuclear supernatant fractions was unchanged
Description: Î?ii-sphet demonstrated no preference for spending more time in proximity to a stranger mouse (stranger 1) versus an empty cage and made significantly fewer entries into the side containing the stranger
