A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly. (28th May 2015)

• Record Type: Journal Article
• 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.
• Is Part Of: Clinical genetics. Volume 88:Number 1(2015:Jul.)
• Page Start: E1
• Page End: E4
• Publication Date: 2015-05-28
• Subjects: Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.12605
• Languages: English
• ISSNs: 0009-9163

Abstract

<abstract abstract-type="main" id="cge12605-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p id="cge12605-para-0001">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 <italic>SLC1A4</italic> (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). <italic>SLC1A4</italic> (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. <sc>l</sc>‐Serine is essential for neuronal survival and differentiation. Indeed, <sc>l</sc>‐serine biosynthesis disorders affect brain development and cause severe ID. In the brain, <sc>l</sc>‐serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of <sc>l</sc>‐serine into neurons and the release of glia‐borne <sc>l</sc>‐serine to neighboring cells. <italic>SLC1A4</italic> disruption may thus impair brain development and function by decreasing the levels of <sc>l</sc>‐serine in neurons. The identification of additional families with mutations in <italic>SLC1A4</italic> would be necessary to confirm its involvement in ID.</p> </abstract>