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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNatureSPTBN1 encodes βII-spectrin, which is a ubiquitously expressed β-spectrin that forms a micron-scale network related to the plasma membrane
.
Mice lacking neuronal βII-spectrin have defects in cortical tissue, developmental delay, and behavioral defects
.
Although these phenotypes are not severe, they have been observed in haploid-deficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also exhibit measurable neurodevelopment and functional impairment
.
On July 1, 2021, Mayo Clinic Margot A.
Cousin and others published a research paper entitled "Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome" in Nature Genetics.
The study identified heterozygous in 29 individuals SPTBN1 variants, these individuals have: developmental, language, and motor developmental delays; mild to severe intellectual disability; autistic features; seizures; behavioral and motor abnormalities; hypotonia; and variable facial features
.
The study showed that these SPTBN1 variants can cause effects that affect the stability of βII-spectrin, disrupt the binding to key molecular partners, and disrupt cytoskeletal organization and dynamics
.
The study defines SPTBN1 variants as the genetic basis of neurodevelopmental syndrome, expands the spectrum of spectrin diseases that affect the brain, and emphasizes the key role of βII-spectrin in the central nervous system
.
Spectrins are ubiquitously expressed, elongated peptides that can bind membrane lipids and ankyrin to align the plasma membrane
.
Spectrin is composed of α-Spectrin and β-Spectrin heterodimer units assembled side by side in an anti-parallel manner, and then forms a head-to-head tetramer, which cross-links F-actin to form a Spectrin-actin array
.
Mammalian neurons express the most diverse species of Spectrin, including αII-Spectrin and all five types of β-Spectrin (βI-V Spectrin)
.
Spectrins self-assemble together with ankyrin, with remarkable long-range regularity and micro- and nano-level specificity to accurately locate and stabilize cell adhesion molecules, membrane transporters, ion channels and other scaffold proteins
.
Some Spectrins can also achieve intracellular organelle transport
.
Unsurprisingly, Spectrin's defects are the basis of several neurodevelopmental and neurodegenerative diseases
.
For example, autosomal dominant genetic variants in βIII-Spectrin (encoded by SPTBN2) cause delayed spinocerebellar ataxia 5 (SCA5), while pathogenic new variants are associated with infantile ataxia, mental retardation, and developmental delay (DD) Related
.
Similarly, autosomal recessive SPTBN2 variants are associated with childhood ataxia, which may also occur in mental retardation and DD
.
The de novo pathogenic variant encoding αII-Spectrin in SPTAN1 causes childhood epilepsy syndromes, including West syndrome, which is an early infantile epileptic encephalopathy characterized by frequent severe seizures and persistent cortical dysfunction
.
Some people also suffer from spastic tetraplegia, DD, and various brain defects
.
In addition, dominantly inherited SPTAN1 nonsense variants can lead to adolescent-onset hereditary motor neuropathy
.
The biallelic change in βIV-Spectrin (encoded by SPTBN4) causes congenital hypotonia, neuropathy, and deafness, with or without intellectual disability
.
The neuron βII-Spectrin encoded by SPTBN1 is the most abundant β-Spectrin in the brain.
It forms a tetramer with αII-Spectrin and inserts the F-actin ring to construct the submembrane cycle skeleton (MPS)
.
The cytoplasmic pool of βII-Spectrin promotes bidirectional axonal organelle transport
.
Mice lacking βII-Spectrin in all neural progenitor cells (Sptbn1flox/flox; Nestin-Cre; called βII-Sp KO) showed early postpartum mortality, reduced long-distance cortical and cerebellar connectivity, spontaneous seizures, and Movement disorders
.
However, the effect of human genetic variants in SPTBN1 on βII-Spectrin function and its association with diseases have not been studied yet
.
The study described a cohort of 29 SPTBN1 individuals with rare, mainly new-onset variants affected by autosomal dominant nervous system syndrome and delays in overall development, language, and movement; mild to severe intellectual disability; Features of autism; seizures; abnormal behavior; hypotonia and variable deformities
.
This indicates the conservative role of βII-Spectrin in neuronal development and function
.
Functional studies have shown that SPTBN1 variants affect protein stability, disrupt binding to key protein partners, and affect cytoskeletal organization and dynamics
.
Therefore, histological and behavioral studies of brain βII Spectrin-deficient mice summarize the developmental and behavioral phenotypes of individuals with SPTBN1 variants
.
In general, the research data strongly supports that the pathogenic mechanism of SPTBN1 mutation is the genetic cause of neurodevelopmental syndrome, and emphasizes the various roles of βII-Spectrin in the nervous system
.
Reference message: https://
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNatureSPTBN1 encodes βII-spectrin, which is a ubiquitously expressed β-spectrin that forms a micron-scale network related to the plasma membrane
.
Mice lacking neuronal βII-spectrin have defects in cortical tissue, developmental delay, and behavioral defects
.
Although these phenotypes are not severe, they have been observed in haploid-deficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also exhibit measurable neurodevelopment and functional impairment
.
On July 1, 2021, Mayo Clinic Margot A.
Cousin and others published a research paper entitled "Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome" in Nature Genetics.
The study identified heterozygous in 29 individuals SPTBN1 variants, these individuals have: developmental, language, and motor developmental delays; mild to severe intellectual disability; autistic features; seizures; behavioral and motor abnormalities; hypotonia; and variable facial features
.
The study showed that these SPTBN1 variants can cause effects that affect the stability of βII-spectrin, disrupt the binding to key molecular partners, and disrupt cytoskeletal organization and dynamics
.
The study defines SPTBN1 variants as the genetic basis of neurodevelopmental syndrome, expands the spectrum of spectrin diseases that affect the brain, and emphasizes the key role of βII-spectrin in the central nervous system
.
Spectrins are ubiquitously expressed, elongated peptides that can bind membrane lipids and ankyrin to align the plasma membrane
.
Spectrin is composed of α-Spectrin and β-Spectrin heterodimer units assembled side by side in an anti-parallel manner, and then forms a head-to-head tetramer, which cross-links F-actin to form a Spectrin-actin array
.
Mammalian neurons express the most diverse species of Spectrin, including αII-Spectrin and all five types of β-Spectrin (βI-V Spectrin)
.
Spectrins self-assemble together with ankyrin, with remarkable long-range regularity and micro- and nano-level specificity to accurately locate and stabilize cell adhesion molecules, membrane transporters, ion channels and other scaffold proteins
.
Some Spectrins can also achieve intracellular organelle transport
.
Unsurprisingly, Spectrin's defects are the basis of several neurodevelopmental and neurodegenerative diseases
.
For example, autosomal dominant genetic variants in βIII-Spectrin (encoded by SPTBN2) cause delayed spinocerebellar ataxia 5 (SCA5), while pathogenic new variants are associated with infantile ataxia, mental retardation, and developmental delay (DD) Related
.
Similarly, autosomal recessive SPTBN2 variants are associated with childhood ataxia, which may also occur in mental retardation and DD
.
The de novo pathogenic variant encoding αII-Spectrin in SPTAN1 causes childhood epilepsy syndromes, including West syndrome, which is an early infantile epileptic encephalopathy characterized by frequent severe seizures and persistent cortical dysfunction
.
Some people also suffer from spastic tetraplegia, DD, and various brain defects
.
In addition, dominantly inherited SPTAN1 nonsense variants can lead to adolescent-onset hereditary motor neuropathy
.
The biallelic change in βIV-Spectrin (encoded by SPTBN4) causes congenital hypotonia, neuropathy, and deafness, with or without intellectual disability
.
The neuron βII-Spectrin encoded by SPTBN1 is the most abundant β-Spectrin in the brain.
It forms a tetramer with αII-Spectrin and inserts the F-actin ring to construct the submembrane cycle skeleton (MPS)
.
The cytoplasmic pool of βII-Spectrin promotes bidirectional axonal organelle transport
.
Mice lacking βII-Spectrin in all neural progenitor cells (Sptbn1flox/flox; Nestin-Cre; called βII-Sp KO) showed early postpartum mortality, reduced long-distance cortical and cerebellar connectivity, spontaneous seizures, and Movement disorders
.
However, the effect of human genetic variants in SPTBN1 on βII-Spectrin function and its association with diseases have not been studied yet
.
The study described a cohort of 29 SPTBN1 individuals with rare, mainly new-onset variants affected by autosomal dominant nervous system syndrome and delays in overall development, language, and movement; mild to severe intellectual disability; Features of autism; seizures; abnormal behavior; hypotonia and variable deformities
.
This indicates the conservative role of βII-Spectrin in neuronal development and function
.
Functional studies have shown that SPTBN1 variants affect protein stability, disrupt binding to key protein partners, and affect cytoskeletal organization and dynamics
.
Therefore, histological and behavioral studies of brain βII Spectrin-deficient mice summarize the developmental and behavioral phenotypes of individuals with SPTBN1 variants
.
In general, the research data strongly supports that the pathogenic mechanism of SPTBN1 mutation is the genetic cause of neurodevelopmental syndrome, and emphasizes the various roles of βII-Spectrin in the nervous system
.
Reference message: https://
