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- Title
A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly.
- Authors
Srour, M.; Hamdan, F. F.; Gan‐Or, Z.; Labuda, D.; Nassif, C.; Oskoui, M.; Gana‐Weisz, M.; Orr‐Urtreger, A.; Rouleau, G.A.; Michaud, J.L.
- 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.
- Subjects
GENETIC mutation; MICROCEPHALY; INTELLECTUAL disabilities; SIBLINGS; GLUTAMATE transporters; ASHKENAZIM; GENOMICS; GENETICS
- Publication
Clinical Genetics, 2015, Vol 88, Issue 1, pE1
- ISSN
0009-9163
- Publication type
Article
- DOI
10.1111/cge.12605