Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1 Velina Guergueltcheva, Dimitar N. Azmanov,

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Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1 Velina Guergueltcheva, Dimitar N. Azmanov, Dora Angelicheva, Katherine R. Smith, Teodora Chamova, Laura Florez, Michael Bynevelt, Thai Nguyen, Sylvia Cherninkova, Veneta Bojinova, Ara Kaprelyan, Lyudmila Angelova, Bharti Morar, David Chandler, Radka Kaneva, Melanie Bahlo, Ivailo Tournev, Luba Kalaydjieva The American Journal of Human Genetics Volume 91, Issue 3, Pages 553-564 (September 2012) DOI: 10.1016/j.ajhg.2012.07.019 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree Structure of the Ataxia-Affected Families Participating in the Study The study included five unrelated Roma families, of which V, M, and B were recruited first and were included in the exome-sequencing analysis. “WES” designates individuals selected for exome sequencing. All participating subjects were genotyped for the GRM1 mutations. The following abbreviations are used: del, presence of c.2652_2654del; N, absence of c.2652_2654del; T, normal allele; and G, mutant allele of c.2660+2T>G. The American Journal of Human Genetics 2012 91, 553-564DOI: (10.1016/j.ajhg.2012.07.019) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Brain Imaging of the Patients with Congenital Cerebellar Ataxia The MRI data were obtained with 1.5T magnetic resonance imagers. (A) Generalized cerebellar atrophy and inferior vermian hypoplasia in patient P II-2 (T1 3D brain volume [BRAVO] with multiplanar reformats [MPRs], coronal T2, and axial T2 sequences). (B) Moderate to severe cerebellar atrophy and inferior vermian hypoplasia in patient B IV-3 (volumetric coronal and sagittal T1 MPR). (C) Evolution of MRI changes in patient V III-2. The left panel shows normal findings at age 1 year and 8 months, and the right panel shows moderate to marked cerebellar atrophy (T1 midline sagittal, T2 sagittal) evident at 6 years of age. The American Journal of Human Genetics 2012 91, 553-564DOI: (10.1016/j.ajhg.2012.07.019) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Genomic Organization of GRM1 and Location of the Ataxia Mutations The upper panel (adapted from Ferraguti et al.34) shows alternative transcripts encoding the most abundant receptor isoforms, mGluR1α and mGluR1β1. Exons 1–8 are invariably included in all GRM1 transcripts, whereas downstream differences—inclusion or skipping of exon 9 and the usage of alternative splice acceptor sites in exon 10—are used for producing the receptor isoforms.34–36 The c.2660+2T>G mutation affects the intron 8 donor splice site, involved in generating all alternative transcripts. The lower panel shows potential consequences of the c.2660+2T>G mutation. In the surrounding sequence, alternative sites that are identified by the Human Splicing Finder tool as donor splice sites and that could be utilized in the absence of the normal signal are indicated in bold lowercase letters. The c.2652_2654del deletion and the novel splice site created as a result are shown with a bracket. In the absence of the normal splice signal, aberrant transcripts could also extend into intron 8 and use a downstream in-frame stop codon (underlined). The American Journal of Human Genetics 2012 91, 553-564DOI: (10.1016/j.ajhg.2012.07.019) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 GRM1 Alternative Transcripts in Normal and Ataxia Cells The left panel shows agarose gel electrophoresis of RT-PCR products. Primers in GRM1 exons 7 and 10 targeted the most abundant alternative transcripts encoding isoforms mGluR1α (skipping exon 9; expected fragment size is 1,030 bp) and mGluR1β (including exon 9; expected size is 1,115 bp). In ataxia cells, the expected fragments are replaced by products less than 200 bp in size. The right panel shows Sanger sequencing of the RT-PCR products in normal and ataxia LCLs. Sequencing was performed on purified products excised from the gel; the forward RT-PCR primer in exon 7 was used for ataxia LCLs, and a nested primer in exon 8 was used for controls. Transcript identity was confirmed in the control cells (derived from a subject heterozygous for the rare SNP rs362936 [G>A]). In ataxia cells, exon 8 was skipped and the transcripts extended from exon 7 into exons 9 and 10. Fragments resulting from the use of the cryptic splice site in exon 8 (expected sizes are 824 bp and 909 bp) or of the novel splice site created by the deletion (expected sizes are 1,020 bp and 1,105 bp) were not detected. The American Journal of Human Genetics 2012 91, 553-564DOI: (10.1016/j.ajhg.2012.07.019) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 5 GRM1 Transcripts Extending from Exon 8 into Intron 8 The left panel shows gel electrophoresis of RT-PCR products with the use of primers in exon 7 and intron 8. Fragments of the expected size (1,144 bp) were observed in all cells. The right panel shows Sanger sequencing of the gel-purified fragments with a nested primer close to the normal junction of exon 8 and intron 8. The product observed in control LCLs and the brain could be identical to a previously described GRM1 transcript and its protein product,41 where the donor splice site of intron 8 is ignored and the immediately following termination codon (boxed) is utilized. In ataxia cells, a downstream in-frame termination codon (shaded) might be used for producing truncated receptor molecules. The American Journal of Human Genetics 2012 91, 553-564DOI: (10.1016/j.ajhg.2012.07.019) Copyright © 2012 The American Society of Human Genetics Terms and Conditions