Intellectual disability or overall developmental delay (ID/GDD) is a major category of neurological developmental diseases with high clinical and genetic heterogeneity, with a prevalence of up to 1% of the population 【1】. In recent years, with the development and application of second-generation sequencing technology, many ID/GDD pathogenic genes have been identified and discovered, but about 60% of ID/GDD patients still have unknown causes.
Recently, a research team led by Texas Children's Hospital Jan Dan Duncan Institute of Neurology (NRI) Researcher and outstanding professor at Baylor College of Medicine Hugo Bellen Ph.D. led by Dr. Dr. in American Journal of Human Genetics published an article in the journal The recurrent de novo c.2011CT missense variant in MTSS2 causes syndromic intellectual disability , reports a novel mental disability syndrome. This study provides the first experimental evidence that this intellectual disability syndrome is caused by spontaneous mutations in the MTSS2 gene.
The study started with a pediatric case in the undiagnosed disease network (UDN, https://undiagnosed.hms.harvard.edu/) that could not be confirmed clinically diagnosed. UDN is a collaborative research team that brings together clinical and research experts from across the United States to address the most challenging rare disease cases using advanced technologies. The network helps patients who are often tested for years but whose medical conditions are still not clearly diagnosed, which severely limits their choice of receiving appropriate clinical treatment and support.
Through genome pairing tools such as MatchMaker Exchange, the researchers identified a cohort of 5 patients with similar symptoms. These patients have symptoms such as developmental delay, intellectual disability, eye movement defects or blindness, (relative) microcephaly and facial features. Exome sequencing showed that they all had the same hybrid mutation of the MTSS2 gene, causing a single amino acid change in the single copy of MTSS2 protein (p.Arg671Trp; Table 1).
is known to MTSS2 generally express in the human brain (GTex, https://www.gtexportal.org/home/). Previous studies in mice showed that this gene highly expresses during the development of the central nervous system [2]. However, prior to this study, the gene had no clear association with human diseases and little was known about its biological effects.
Based on existing human gene big data analysis, the prediction shows that the p.Arg671Trp point mutation may have a detrimental impact on the function of the MTSS2, and the amino acid p.Arg671 is conserved in the homologous proteins of various species, thus providing clues for the possible symptoms of the mutation in patients. In addition, the team found that although this genetic variant reduced the levels of transcript mRNA in patient cells, it did not reduce the levels of the MTSS2 protein it encoded, suggesting that the variant MTSS2 protein may have an effect in the patient.
Drug flies as diagnostic tool
To study whether mutations in the MTSS2 gene are the cause of these patients, researchers in Bellen's laboratory used the fruit flies of this gene ( peas, fruit flies and humans - using fruit flies to diagnose a large number of rare genetic diseases ) version "missing in metastasism 3" (mim) for the study.They constructed mutant fruit flies that destroyed the m gene by inserting GAL4 using CRISPR-CAS9, and constructed transgenic fruit flies that expressed the human MTSS2 gene. The study found that the m gene is expressed in many neurons and partial glial cells of fruit fly. m functionally inactivated mutant flies shortened their lifespan, impaired exercise and vision, and have mild susceptibility to epilepsy. After expressing the human MTSS2 gene in these mutant fruit flies, the above defects can be restored, indicating that the functions of fruit flies mim and human MTSS2 are conservative. When the patient's mutant MTSS2 was expressed in the same way in the m mutant, there was no significant recovery of functional defect, indicating that the function of the mutant MTSS2 protein was reduced.
Interestingly, they found that if the mutation in patients with excessive expression in wild-type fruit flies MTSS2 can lead to very similar functional defects to the inactivated mutant of mim. In contrast, excessive expression of normal MTSS2 did not cause these defects. These findings suggest that the p.Arg671Trp mutant protein may cause symptoms observed in patients by interfering with the function of normal proteins, i.e., in a dominant negative effect.
This study combined with in-depth clinical evaluation, exome sequencing and fruit fly functional studies, found that the disruption of MTSS2 protein function may be the cause of symptoms in these patients. This is the first experimental evidence for the role of MTSS2 in neurological diseases and provides the basis for further dissecting the underlying mechanisms. Dr. Huang Yan, a postdoctoral fellow in the
Bellen Laboratory, Gabrielle Lemire, MD, CHEO, Canada, and Lauren Briere, MS, of the Children's Hospital of Massachusetts General Hospital, are co-first authors of this study.
Original link:
https://doi.org/10.1016/j.ajhg.2022.08.011
Platemaker: eleven
References
1. Boyle, C.A., Boulet, S., Schieve, L.A., Cohen, R.A., Blumberg, S.J., Yeargin-Allsopp, M., Visser, S., and Kogan, M.D. (2011). Trends in the prevalence of developmental disabilities in US children, 1997-2008. Pediatrics 127, 1034-1042.
. Saarikangas, J., Hakanen, J., Mattila, P.K., Grumet, M., Salminen, M., and Lappalainen, P. (2008). ABBA regulates plasma-membrane and actin dynamics to promote radial glia extension. J Cell Sci 121, 1444-1454.
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