High Prevalence of SLC6A8 Deficiency in X-Linked Mental Retardation

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High Prevalence of SLC6A8 Deficiency in X-Linked Mental Retardation Efraim H. Rosenberg, Ligia S. Almeida, Tjitske Kleefstra, Rose S. deGrauw, Helger G. Yntema, Nadia Bahi, Claude Moraine, Hans- Hilger Ropers, Jean-Pierre Fryns, Ton J. deGrauw, Cornelis Jakobs, Gajja S. Salomons The American Journal of Human Genetics Volume 75, Issue 1, Pages 97-105 (July 2004) DOI: 10.1086/422102 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Mutations and polymorphisms in patients with XLMR. Primer sequences were designed specifically to amplify all exons of the SLC6A8 gene (and not the SLC6A10 gene, a presumed creatine transporter pseudogene mapped at chromosome 16 [Eichler et al. 1996]), including short fragments of the flanking intronic sequences. By comparing the SLC6A8 and SLC6A10 sequences, we have found that at least two nucleotide variations were present in all amplicons, confirming selective amplification of the SLC6A8 sequences (data not shown). PCR reactions were performed with HotStar Taq (Qiagen) in a PE Applied Biosystems model 9700. Direct sequence analysis was performed on purified PCR products (Millipore vacufold) by use of BigDye v3.1 terminators and an ABI 3100 sequence machine (PE Applied Biosystems). The obtained electropherograms were assembled and analyzed to identify potential genomic alterations by use of the Mutation Surveyor software package (SoftGenetics). Sequence variants were annotated according the guidelines of den Dunnen and Antonarakis (2001). On the basis of impaired uptake in fibroblasts, five alterations (asterisks [*]) have been proven elsewhere to be mutations. p.F107del was also found in our XLMR cohort. One novel nonsense mutation (p.Y317X) is strongly predictive of impaired creatine uptake. p.M560V is a rare polymorphism, and p.V629I is an unclassified variant. The implications of the translational silent variant, the IVS variant, and the 3′ UTR variant could not yet be investigated, and these variants are therefore assigned as “unclassified.” IVS variants in introns 1, 2, 3, and 4 may have been missed, since only small exon-flanking parts were included. The American Journal of Human Genetics 2004 75, 97-105DOI: (10.1086/422102) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Multiple-sequence alignment with hierarchical clustering among the SLC6A8 proteins of different species and the superfamily of neurotransmitter transporters. The SLC6A8 protein sequence is shown for the following species: Homo sapiens (A8), Rattus norvegicus (RN), Mus musculus (MM), Bos taurus (BT), Oryctolagus cuniculus (OC), and Torpedo marmorata (TM). SLC6A8 genes were identified by a protein blast (BLASTP). Alignment was determined by the ClustalW program; the SLC6A8 proteins that were used for this analysis were the ones identified by the BLASTP search to be most related to the Homo sapiens SLC6A8 protein. All were saved in FASTA format. The BOXSHADE program was used to visualize identical amino acids (highlighted in black) and functionally conserved amino acids (gray). Functionally conserved amino acids are classified as follows: V, I, L, and M; D, E, Q, and N; F, Y, and W; G, S, T, P, and A; and K, R, and H. The codes A1–A14 represent neurotransmitter transporters SLC6A1–SLC6A14 (A1 = GABA1, A2 = noradrenaline, A3 = dopamine, A4 = serotonine, A5 = glycine2, A6 = taurine, A7 = proline, A9 = glycine 1, A11 = GABA3, A12 = betaine/GABA, A13 = GABA2, and A14 = ATB0+). In the protein sequence of A5, certain amino acids (20–46, 51–93, 116–127, 143–152, and 168–184) were cut out, because these stretches occur only in SLC6A5 and would make the figure disorganized. TMI–TMXII = putative transmembrane domain, predicted by ExPASy (Swiss-Prot S6A8_Human P48029); ♦ = putative cAMP-PK phosphorylation site (2×); ▴ = putative N-glycosylation sites (3×); ▪ = putative Leu zipper motif (4×). The American Journal of Human Genetics 2004 75, 97-105DOI: (10.1086/422102) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Multiple-sequence alignment with hierarchical clustering among the SLC6A8 proteins of different species and the superfamily of neurotransmitter transporters. The SLC6A8 protein sequence is shown for the following species: Homo sapiens (A8), Rattus norvegicus (RN), Mus musculus (MM), Bos taurus (BT), Oryctolagus cuniculus (OC), and Torpedo marmorata (TM). SLC6A8 genes were identified by a protein blast (BLASTP). Alignment was determined by the ClustalW program; the SLC6A8 proteins that were used for this analysis were the ones identified by the BLASTP search to be most related to the Homo sapiens SLC6A8 protein. All were saved in FASTA format. The BOXSHADE program was used to visualize identical amino acids (highlighted in black) and functionally conserved amino acids (gray). Functionally conserved amino acids are classified as follows: V, I, L, and M; D, E, Q, and N; F, Y, and W; G, S, T, P, and A; and K, R, and H. The codes A1–A14 represent neurotransmitter transporters SLC6A1–SLC6A14 (A1 = GABA1, A2 = noradrenaline, A3 = dopamine, A4 = serotonine, A5 = glycine2, A6 = taurine, A7 = proline, A9 = glycine 1, A11 = GABA3, A12 = betaine/GABA, A13 = GABA2, and A14 = ATB0+). In the protein sequence of A5, certain amino acids (20–46, 51–93, 116–127, 143–152, and 168–184) were cut out, because these stretches occur only in SLC6A5 and would make the figure disorganized. TMI–TMXII = putative transmembrane domain, predicted by ExPASy (Swiss-Prot S6A8_Human P48029); ♦ = putative cAMP-PK phosphorylation site (2×); ▴ = putative N-glycosylation sites (3×); ▪ = putative Leu zipper motif (4×). The American Journal of Human Genetics 2004 75, 97-105DOI: (10.1086/422102) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 Pedigree charts of families in which segregation could be studied. (For designation of the variants, see table 1.) The American Journal of Human Genetics 2004 75, 97-105DOI: (10.1086/422102) Copyright © 2004 The American Society of Human Genetics Terms and Conditions