Molecular Characterization of WFS1 in Patients with Wolfram Syndrome

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Thomas M. Williams The Journal of Molecular Diagnostics

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Molecular Characterization of WFS1 in Patients with Wolfram Syndrome Johannes M.W. Van Den Ouweland, Kim Cryns, Ronald J.E. Pennings, Inge Walraven, George M.C. Janssen, J. Antonie Maassen, Bernard F.E. Veldhuijzen, Alexander B. Arntzenius, Dick Lindhout, Cor W.R.J. Cremers, Guy Van Camp, Lambert D. Dikkeschei The Journal of Molecular Diagnostics Volume 5, Issue 2, Pages 88-95 (May 2003) DOI: 10.1016/S1525-1578(10)60457-6 Copyright © 2003 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 1 The pedigrees of Wolfram families WF1 to WF9. The first line below each symbol represents generation (roman numeral) and identification number. −, Absence of WFS1 mutation; +, presence of WFS1 mutation; ND, not determined. The Journal of Molecular Diagnostics 2003 5, 88-95DOI: (10.1016/S1525-1578(10)60457-6) Copyright © 2003 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 2 Alternative splicing site in WFS1 resulting in the deletion of four nucleotides (GCAG). A: Sequence chromatograms of the reverse transcriptase-PCR fragment of a control and of patient II-1 of WF9. Besides the normal sequence, a second sequence with the GCAG deletion is present accounting for ∼30 to 40% in patient II-1 of WF9 and to a lesser extent in a control (<10%). B and C: Schematic diagram of the normal (B) and alternative (C) splicing mechanisms in WFS1. Boxes denote exons. Normal (B) and alternative (C) acceptor splice sites are underlined. Alternative splicing in C is shown by the thickened line. The initiator codon is in bold. Intron and exon sequences are shown in lower and upper case letters, respectively. D: Effect of the alternative splicing on the sequences flanking the initiation codon. Translation initiation signal sequences are shown of the normal WFS1 transcript,2 the variant WFS1 transcript,3 and of the consensus1 as proposed by Kozak.26 Numbers denote position from the A(+1)TG initiator sequence. Arrows mark difference between the normal WFS1 sequence and the sequence that results from alternative splicing. The Journal of Molecular Diagnostics 2003 5, 88-95DOI: (10.1016/S1525-1578(10)60457-6) Copyright © 2003 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 3 Hypothetical structure of wolframin (WFS1), and positions of mutations detected in Dutch families. The amino acid sequence of wolframin (GenBank accession number Y18064) was analyzed for hydrophobicity with the transmembrane prediction program, TMpred. Gray circles denote hydrophilic domains, and the white circles denote the best predicted transmembrane domains. Black circles denote amino acid residues that were deleted or mutated to stop codons, or sites of missense mutations. The black triangle denotes the putative stop codon resulting from the splice-donor site mutation in family WF1. The figure has been modified from Hardy and colleagues.15 The Journal of Molecular Diagnostics 2003 5, 88-95DOI: (10.1016/S1525-1578(10)60457-6) Copyright © 2003 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions