Drosophila studies contribute to understanding impact of a variant of MTSS2 associated with intellectual disability

Am J Hum Genet. 2022 Aug 30:S0002-9297(22)00363-9. doi: 10.1016/j.ajhg.2022.08.011.

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

Huang Y, Lemire G, Briere LC, Liu F, Wessels MW, Wang X, Osmond M, Kanca O, Lu S, High FA, Walker MA, Rodan LH; Undiagnosed Diseases Network; Care4Rare Canada Consortium, Kernohan KD(, Sweetser DA, Boycott KM, Bellen HJ

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.

DOI: 10.1016/j.ajhg.2022.08.011
PMID: 36067766

Drosophila as "a fundamental genetic model to identify new disease-causing variants" -- review from Bellen, Wangler & Yamamoto

Bellen HJ, Wangler MF, Yamamoto S. The fruit fly at the interface of diagnosis and pathogenic mechanisms of rare and common human diseases. Hum Mol Genet. 2019 Jun 22. pii: ddz135. doi: 10.1093/hmg/ddz135. PubMed PMID: 31227826.

Abstract: "Drosophila melanogaster is a unique, powerful genetic model organism for studying a broad range of biological questions. Human studies that probe the genetic causes of rare and undiagnosed diseases using massive-parallel sequencing often require complementary gene function studies to determine if and how rare variants affect gene function. These studies also provide inroads to disease mechanisms and therapeutic targets. In this review we discuss strategies for functional studies of rare human variants in Drosophila. We focus on our experience in establishing a Drosophila Core for the Model Organisms Screening Center (MOSC) for the Undiagnosed Diseases Network (UDN) and concurrent fly studies with other large genomic rare disease research efforts such as the Centers for Mendelian Genomics (CMG). We outline four major strategies that use the latest technology in fly genetics to understand the impact of human variants on gene function. We also mention general concepts in probing disease mechanisms, therapeutics and using rare disease to understand common diseases. Drosophila is and will continue to be a fundamental genetic model to identify new disease-causing variants, pathogenic mechanisms and drugs that will impact medicine."

Drosophila studies help elucidate the genetic nature of disease-associated variants--study from the NIH Undiagnosed Diseases Network

Liu N, Schoch K, Luo X, Pena LDM, Bhavana VH, Kukolich MK, Stringer S, Powis Z, Radtke K, Mroske C, Deak KL, McDonald MT, McConkie-Rosell A, Markert ML, Kranz PG, Stong N, Need AC, Bick D, Amaral MD, Worthey EA, Levy S; Undiagnosed Diseases Network (UDN), Wangler MF, Bellen HJ, Shashi V, Yamamoto S. Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder. Hum Mol Genet. 2018 Jul 15;27(14):2454-2465. PMID: 29726930; PMCID: PMC6030957.

Abstract: "The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.2 deletion. We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants. The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Bioinformatics analyses indicate that these variants are rare and predict them to be damaging. In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2. Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles. Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder."

Drosophila research studies contribute to patient diagnosis for patients with previously undiagnosed diseases

Splinter et al. Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. New England Journal of Medicine. DOI: 10.1056/NEJMoa1714458

This article, which can be accessed free at NEJM, includes a description of how studies in Drosophila and other model systems contribute to identification by the Undiagnosed Diseases Network of disease-causing variants in genome data from previously undiagnosed patients. As stated in the article, "The model organisms screening center was directly involved in the diagnosis of eight patients in this study."