Novel compound heterozygous mutation in STAMBP causes a neurodevelopmental disorder by disrupting cortical
Meixin Hu1, Huiping Li1, Zhuxi Huang2,3
1Department of Child Health Care, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Insights
STAMBP gene mutations cause developmental delays and microcephaly. A novel mutation impairs neural stem cell proliferation, highlighting variable STAMBP phenotypes and their impact on brain development.
Area of Science:
- Genetics
- Developmental Biology
- Neuroscience
Background:
- Mutations in the STAMBP gene, encoding STAM-binding protein, are linked to developmental delay, microcephaly, and capillary malformations.
- Limited case reports necessitate further investigation into the functional and phenotypic spectrum of STAMBP variants.
Purpose of the Study:
- To investigate the pathogenicity of novel STAMBP mutations.
- To elucidate the role of STAMBP in human brain development using a 3D cortical organoid model.
Main Methods:
- Whole exome sequencing identified compound heterozygous STAMBP mutations in a patient with a neurodevelopmental disorder.
- Sanger sequencing validated the mutations.
- 3D human cortical organoids were utilized to assess STAMBP function and the pathogenicity of a specific missense mutation.
Main Results:
- STAMBP knockout cortical organoids exhibited reduced neural stem cell proliferation, resulting in smaller organoids consistent with microcephaly.
- STAMBP disruption did not impact early apoptosis.
- Re-expression of wild-type STAMBP, but not the identified missense mutation or a known pathogenic mutation, rescued the impaired proliferation in STAMBP-deficient organoids.
Conclusions:
- STAMBP mutations present a variable clinical phenotype with differing symptom severity.
- The novel STAMBP missense mutation identified impairs neural stem cell proliferation, contributing to neurodevelopmental deficits in human brain development.
Background:
Mutations in the STAMBP gene, which encodes a deubiquitinating isopeptidase called STAM-binding protein, are related to global developmental delay, microcephaly, and capillary malformation. Owing to the limited number of reported cases, the functional and phenotypic characteristics of STAMBP variants require further elucidation.
Materials And Methods:
Whole exome sequencing was performed on a patient presenting with a neurodevelopmental disorder. Novel compound heterozygous mutations in STAMBP [c.843_844del (p.C282Wfs*11) and c.920G > A (p.G307E)] were identified and validated using Sanger sequencing. A 3D human cortical organoid model was used to investigate the function of STAMBP and the pathogenicity of the novel mutation (c.920G > A, p.G307E).
Results:
The patient was presented with global developmental delay, autism spectrum disorder, microcephaly, epilepsy, and dysmorphic facial features but without apparent capillary malformation on the skin and organs. Cortical organoids with STAMBP knockout (KO) showed significantly lower proliferation of neural stem cells (NSCs), leading to smaller organoids that are characteristic of microcephaly. Furthermore, STAMBP disruption did not affect apoptosis in early cortical organoids. After re-expressing wild-type STAMBP, STAMBP , and STAMBP (a known pathogenic mutation) within STAMBP KO organoids, only STAMBP rescued the impaired proliferation of STAMBP deficient organoids, but not STAMBP and STAMBP .
Conclusion:
Our findings demonstrate that the clinical phenotype of STAMBP mutations is highly variable, and patients with different STAMBP mutations show differences in the severity of symptoms. The STAMBP missense mutation identified here is a novel pathogenic mutation that impairs the proliferation of NSCs in human brain development.
