Novel compound heterozygous mutation in STAMBP causes a neurodevelopmental disorder by disrupting cortical proliferation

Meixin Hu; Huiping Li; Zhuxi Huang; Dongyun Li; Ying Xu; Qiong Xu; Bo Chen; Yi Wang; Jingxin Deng; Ming Zhu; Weijun Feng; Xiu Xu

doi:10.3389/fnins.2022.963813

Novel compound heterozygous mutation in STAMBP causes a neurodevelopmental disorder by disrupting cortical proliferation

Front Neurosci. 2022 Aug 10:16:963813. doi: 10.3389/fnins.2022.963813. eCollection 2022.

Authors

Meixin Hu¹, Huiping Li¹, Zhuxi Huang^{2

3}, Dongyun Li¹, Ying Xu^{2

3}, Qiong Xu¹, Bo Chen^{2

3}, Yi Wang¹, Jingxin Deng¹, Ming Zhu^{2

3}, Weijun Feng^{2

3}, Xiu Xu¹

Affiliations

¹ Department of Child Health Care, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
² Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China.
³ Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.

Abstract

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 ^G307E , and STAMBP ^T313I (a known pathogenic mutation) within STAMBP KO organoids, only STAMBP ^WT rescued the impaired proliferation of STAMBP deficient organoids, but not STAMBP ^G307E and STAMBP ^T313I .

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.

Keywords: STAMBP; cortical organoids; microcephaly; neurodevelopmental disorder; novel mutation.