Two Exon-Skipping Mutations as the Molecular Basis of Succinic Semialdehyde Dehydrogenase Deficiency (4-Hydroxybutyric Aciduria) Ken L. Chambliss, Debra.

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Two Exon-Skipping Mutations as the Molecular Basis of Succinic Semialdehyde Dehydrogenase Deficiency (4-Hydroxybutyric Aciduria) Ken L. Chambliss, Debra D. Hinson, Flavia Trettel, Patrizia Malaspina, Andrea Novelletto, Cornelis Jakobs, K. Michael Gibson The American Journal of Human Genetics Volume 63, Issue 2, Pages 399-408 (August 1998) DOI: 10.1086/301964 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 GABA degradative pathway. 1 = GABA-transaminase; 2 = SSADH; and 3 = one or more 4-hydroxybutyrate dehydrogenases. The cross-hatched box denotes the site of the defect in patients with SSADH deficiency. The American Journal of Human Genetics 1998 63, 399-408DOI: (10.1086/301964) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 Nucleotide and deduced amino acid sequence of human SSADH. Nucleotides and amino acid residues are numbered to the right, with the first residue of the mature protein being boxed and numbered as “+1.” The positions of the nine introns that split the coding region were determined by comparison of cDNA and genomic clones and are indicated by vertical lines. This sequence has been deposited in GenBank (accession number Y11192). The American Journal of Human Genetics 1998 63, 399-408DOI: (10.1086/301964) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 RT-PCR products from five patients with 4-hydroxybutyric aciduria, their family members, and a control, analyzed on an ethidium bromide–stained agarose gel. The amplicon from a normal SSADH cDNA is 638 bp. Three of the patients exhibit a visibly smaller product, whereas their parents and unaffected siblings have both RT-PCR products, indicating heterozygosity. Two unrelated patients have the wild-type–size amplicon. Lane M, Molecular-weight size standards. Lane 1, Control. Lane 2, Patient ZZ. Lane 3, Father of ZZ. Lane 4, Mother of ZZ. Lane 5, Brother of ZZ. Lane 6, Sister of ZZ. Lane 7, Patient OD. Lane 8, Patient DP (sister of OD). Lane 9, Father of OD and PD; Lane 10, Mother of OD and PD. Lane 11, Brother of OD and PD. Lane 12, Unrelated patient SM. Lane 13, SM mother. Lane 14, Unrelated patient IA. The American Journal of Human Genetics 1998 63, 399-408DOI: (10.1086/301964) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 4 RT-PCR products from patient AC (lane 3), his parents (lanes 1 and 2), and a control (lane 4), analyzed on an agarose gel. Lane M, Size standards. The dominant product obtained from the control sample is 632 bp, whereas the single product from PCRs of the patient is 144 bp smaller (i.e., 488 bp). The intermediate-size product was shown to be artifactual and independent of RNA template. The American Journal of Human Genetics 1998 63, 399-408DOI: (10.1086/301964) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 5 DNA sequence of representative RT-PCR products from the gel in figure 3. The larger band consistently contained the wild-type SSADH cDNA sequence, whereas the smaller amplicon consistently exhibited a complete deletion of the 59-bp exon 9. The American Journal of Human Genetics 1998 63, 399-408DOI: (10.1086/301964) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 6 Representative DNA sequence of PCR products amplified from genomic DNA of wild-type controls (left), patients (center), and family members of patients (right). The three patients, (ZZ, OD, and PD) all contained a G→T mutation at the first base of intron 9, which alters the 5′ splice site. Family members of patients who exhibited both RT-PCR products proved to be heterozygous for this mutation. The American Journal of Human Genetics 1998 63, 399-408DOI: (10.1086/301964) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 7 DNA sequence of representative RT-PCR products from the gel in figure 4. All lower bands were missing the 144-bp exon 5, whereas the predominant upper band contained wild-type sequence. The less predominant upper band and the intermediate band were shown to be PCR artifacts (see text). The American Journal of Human Genetics 1998 63, 399-408DOI: (10.1086/301964) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 8 Genomic DNA sequence around exon 5 in controls (left), patient AC (center), and patient AC's parents (right), examined by PCR. The single, 271-bp amplicon was directly sequenced. The patient was homozygous for a G→A base change at the first base of intron 5. His parents were heterozygous for the normal G at that position and the mutant A. Controls showed wild-type sequence. The American Journal of Human Genetics 1998 63, 399-408DOI: (10.1086/301964) Copyright © 1998 The American Society of Human Genetics Terms and Conditions