Dominant Inheritance of Sialuria, an Inborn Error of Feedback Inhibition Jules G. Leroy, Raili Seppala, Marjan Huizing, George Dacremont, Helena De Simpel,

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Dominant Inheritance of Sialuria, an Inborn Error of Feedback Inhibition Jules G. Leroy, Raili Seppala, Marjan Huizing, George Dacremont, Helena De Simpel, Rudy N. Van Coster, Edwin Orvisky, Donna M. Krasnewich, William A. Gahl The American Journal of Human Genetics Volume 68, Issue 6, Pages 1419-1427 (June 2001) DOI: 10.1086/320598 Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical features in patient 1. A and B, Proband at age 10.5 mo. Note flat, mildly coarse facies, epicanthal folds, and low nasal bridge; excessive nasal discharge; difficulty sitting without support; and mild axial hypotonia. C and D, Proband at age 4 years. The patient is considerably improved, with significant neuromotor progress. Note accidental scar on nose, absence of facial coarsening, and no limitation of motion in any joints. The American Journal of Human Genetics 2001 68, 1419-1427DOI: (10.1086/320598) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 2 Skeletal radiographs of proband at age 10.5 mo. Note slightly short and wide long-bone diaphyses; squat pubic and ischial bones; osteopenic, mildly short, and coarsely trabeculated metacarpals; and widened metaphyses in the distal ulnae and radii, distal femora, and proximal tibiae. The skeletal age was between 3 and 6 mo. The American Journal of Human Genetics 2001 68, 1419-1427DOI: (10.1086/320598) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 3 CMP-Neu5Ac inhibition of UDP-GlcNAc 2-epimerase activity. The substrate of epimerase is [3H]UDP-GlcNAc, and the product is [3H]ManNAc. [3H]GlcNAc represents a degradation product of [3H]UDP-GlcNAc, not a product of epimerase (Seppala et al. 1992). A, Epimerase activity in normal fibroblasts. Significant ManNAc is formed in the absence of CMP-Neu5Ac (left), and 100 mM CMP-Neu5Ac inhibits ManNAc formation by 95% (right). B, Fibroblast epimerase activity in patient 1. CMP-Neu5Ac, 100 mM (right), did not inhibit ManNAc production at all compared with ManNAc production in the absence of CMP-Neu5Ac (left). The American Journal of Human Genetics 2001 68, 1419-1427DOI: (10.1086/320598) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 4 Molecular diagnosis of sialuria in the family of patient 1. A, Genomic DNA sequencing of patient 1, his father, and his mother (patient 2). At position 848, the father has the normal G, but both the patient and his mother are heterozygous for the G→A substitution. B, Agarose gel electrophoresis of reaction products formed by AciI restriction-enzyme digestion of a 385-bp fragment that includes nucleotide 848. Lane 1, molecular weight markers. Lanes 2 and 3, father’s DNA, uncut (U) and completely cut (C) into 229-bp and 156-bp fragments. Lanes 4–7, DNA from the two unaffected siblings, uncut (lanes 4 and 6) and completely cut (lanes 5 and 7). Lanes 8–11, DNA from the proband (patient 1) and his mother (patient 2), uncut (lanes 8 and 10) and cut (lanes 9 and 11). The cut DNA shows heterozygosity for the normal sequence (229-bp and 156-bp fragments) and the mutation (uncut 385-bp fragment). The American Journal of Human Genetics 2001 68, 1419-1427DOI: (10.1086/320598) Copyright © 2001 The American Society of Human Genetics Terms and Conditions