158 Oral - Models of Human Disease I - Diseases with a Neurological Focus
Saturday April 09, 9:30 AM - 9:45 AM

Authors:
Shenzhao Lu ^1,2,3; Rebecca Hernan ⁴; Paul Marcogliese ^1,2; Yan Huang ^1,2; Tracy Gertler ⁵; Meltem Akcaboy ⁶; Shiyong Liu ⁷; Hyung-lok Chung ^1,2; Xueyang Pan ^1,2; Xiaoqin Sun ⁷; Melek Oguz ⁶; Ulkühan Oztoprak ⁶; Jeroen de Baaij ⁸; Jelena Ivanisevic ⁵; Erin McGinnis ⁵; Maria Guillen Sacoto ⁹; Wendy Chung ^4,10; Hugo Bellen ^1,2

Affiliations:
1) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; 2) Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; 3) Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA ; 4) Department of Pediatrics, Columbia University, New York, NY 10032, USA; 5) Division of Neurology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA; 6) Department of Pediatrics, Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research Hospital, Ankara, Turkey; 7) Department of Neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China; 8) Department of Physiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, 6500HB, the Netherlands; 9) GeneDx, Inc., Gaithersburg, MD 20877, USA; 10) Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA

Keywords:
b. neural disorder; k. developmental disorders

The actin cytoskeleton is essential to maintain basic cell functions. Its dysregulation in neurons often leads to neurological diseases. T-lymphoma invasion and metastasis 1 protein (TIAM1) regulates Rac1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with biallelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay and seizures. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS), and is mainly expressed in a subset of neurons but not in glia. Loss of sif causes a severe reduction in viability, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. Both sif and TIAM1 are toxic when ubiquitously overexpressed in Drosophila. Hence, either loss or gain of function of the gene affects development and survival. We assessed the toxicity associated with three TIAM1 variants carried by two of the probands and compared them to the TIAM1 reference cDNA function in vivo. The data suggest that they are all loss-of-function (LoF) variants: p.L862F is the most severe LoF variant, while p.R23C and p.G328V are less severe LoF variants. In summary, we provide evidence that sif is important for appropriate neural function and that TIAM1 variants observed in the probands are disruptive, thus implicating loss of TIAM1 in neurological phenotypes in humans.