The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability

Yan Huang, Gabrielle Lemire, Undiagnosed Diseases Network, Care4Rare Canada Consortium, Lauren C. Briere, Fang Liu, Marja W. Wessels, Xueqi Wang, Matthew Osmond, Oguz Kanca, Shenzhao Lu, Frances A. High, Melissa A. Walker, Lance H. Rodan, Kristin D. Kernohan, David A. Sweetser, Kym M. Boycott, Hugo J. Bellen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

MTSS2, also known as MTSS1L, binds to plasma membranes and modulates their bending. MTSS2 is highly expressed in the central nervous system (CNS) and appears to be involved in activity-dependent synaptic plasticity. Variants in MTSS2 have not yet been associated with a human phenotype in OMIM. Here we report five individuals with the same heterozygous de novo variant in MTSS2 (GenBank: NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. In summary, our findings support that mim is important for appropriate neural function, and that the MTSS2 c.2011C>T variant causes a syndromic form of intellectual disability.

Original languageEnglish
Pages (from-to)1923-1931
Number of pages9
JournalAmerican Journal of Human Genetics
Volume109
Issue number10
Early online date5 Sep 2022
DOIs
Publication statusPublished - 6 Oct 2022

Bibliographical note

Funding Information:
We thank all of the individuals and their families for their participation, in particular the parents of individual 4, who connected with the UDN directly about this gene. We thank Dr. Xiao Mao for connecting us with the clinician in China. We thank Hongling Pan for the injections to create transgenic flies. Part of this work was performed under the Care4Rare Canada Consortium. G.L. was supported by a Children's Hospital Academic Medical Organization clinical fellowship award through CHEO and by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (grants UM1 HG008900, U01 HG0011755 and R01 HG009141). K.M.B. was supported by a CIHR Foundation Grant (FDN-154279) and a Tier 1 Canada Research Chair in Rare Disease Precision Health. This work was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Direction under award number U01HG007690 (D.A.S. M.A.W. F.A.H. L.C.B. E.T.). The Translational Clinical Research Center at Massachusetts General Hospital was supported by NIH grant number 1UL1TR001102. H.J.B. was supported through the Model Organisms Screening Center of the UDN by U54NS093793 (NINDS), the Office of Research Infrastructure Programs of the NIH (awards R24 OD022005 and R24 OD031447). The content of this paper is solely the responsibility of the authors and does not necessarily represent official views of the NIH. Further acknowledgments are described in the supplemental information. The authors declare no competing interests.

Funding Information:
We thank all of the individuals and their families for their participation, in particular the parents of individual 4, who connected with the UDN directly about this gene. We thank Dr. Xiao Mao for connecting us with the clinician in China. We thank Hongling Pan for the injections to create transgenic flies. Part of this work was performed under the Care4Rare Canada Consortium. G.L. was supported by a Children’s Hospital Academic Medical Organization clinical fellowship award through CHEO and by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (grants UM1 HG008900 , U01 HG0011755 and R01 HG009141 ). K.M.B. was supported by a CIHR Foundation Grant ( FDN-154279 ) and a Tier 1 Canada Research Chair in Rare Disease Precision Health. This work was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Direction under award number U01HG007690 (D.A.S., M.A.W., F.A.H., L.C.B., E.T.). The Translational Clinical Research Center at Massachusetts General Hospital was supported by NIH grant number 1UL1TR001102 . H.J.B. was supported through the Model Organisms Screening Center of the UDN by U54NS093793 (NINDS), the Office of Research Infrastructure Programs of the NIH (awards R24 OD022005 and R24 OD031447 ). The content of this paper is solely the responsibility of the authors and does not necessarily represent official views of the NIH. Further acknowledgments are described in the supplemental information .

Publisher Copyright:
© 2022 American Society of Human Genetics

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