A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly |
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| Authors: | M. Srour F. F. Hamdan Z. Gan‐Or D. Labuda C. Nassif M. Oskoui M. Gana‐Weisz A. Orr‐Urtreger G.A. Rouleau J.L. Michaud |
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| Affiliation: | 1. Division of Pediatric Neurology, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada;2. CHU Sainte‐Justine Research Center, Montreal, Canada;3. Montreal Neurological Institute, McGill University, Montreal, Canada;4. Department of Human Genetics, McGill University, Montreal, Canada;5. Department of Pediatrics, Université de Montréal, Montreal, Canada;6. The Genetic Institute, Tel‐Aviv Sourasky Medical Center, Tel‐Aviv, Israel;7. Sackler Faculty of Medicine, Tel‐Aviv University, Tel‐Aviv, Israel;8. Department of Neurology and Neurosurgery, McGill University, Montreal, Canada;9. Department of Neurosciences, Université de Montréal, Montreal, Canada |
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| Abstract: | We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. l ‐Serine is essential for neuronal survival and differentiation. Indeed, l ‐serine biosynthesis disorders affect brain development and cause severe ID. In the brain, l ‐serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of l ‐serine into neurons and the release of glia‐borne l ‐serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of l ‐serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID. |
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| Keywords: | Ashkenazi Jewish exome sequencing intellectual disability microcephaly neutral amino acid SLC1A4 |
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