Mutations in HPSE2 Cause Urofacial Syndrome

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LRIG2 Mutations Cause Urofacial Syndrome

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Mutations in HPSE2 Cause Urofacial Syndrome Sarah B. Daly, Jill E. Urquhart, Emma Hilton, Edward A. McKenzie, Richard A. Kammerer, Malcolm Lewis, Bronwyn Kerr, Helen Stuart, Dian Donnai, David A. Long, Berk Burgu, Ozgu Aydogdu, Murat Derbent, Sixto Garcia-Minaur, Willie Reardon, Blanca Gener, Stavit Shalev, Rupert Smith, Adrian S. Woolf, Graeme C. Black, William G. Newman The American Journal of Human Genetics Volume 86, Issue 6, Pages 963-969 (June 2010) DOI: 10.1016/j.ajhg.2010.05.006 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Identification of Intragenic Deletion in HPSE2 in an Affected UFS Patient (A) The pedigree of family 1 indicates the individuals who were screened by PCR for a deletion breakpoint, indicated by ∗. Filled-in symbols represent affected individuals, and symbols containing a dot indicate heterozygote. SNP6.0 array performed on IV:4 is indicated by an arrow. (B) Photograph of affected siblings demonstrating characteristic grimace upon smiling. (C) SNP6.0 array copy number analysis illustrating 11 probe deletions in HPSE2. Log2ratio, copy number state (CNState), and red bar all indicate the deleted region, and an ideogram of chromosome 10 with the position of the deletion is indicated by a red triangle. The American Journal of Human Genetics 2010 86, 963-969DOI: (10.1016/j.ajhg.2010.05.006) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification of HPSE2 Mutations in UFS Families Pedigrees and genomic sequence chromatograms of families 2, 3, 4, and 6. In family 2, a homozygous nonsense mutation in exon 10 (p.R472X) was identified; in family 3, a frameshift mutation as a result of a homozygous single base pair insertion in exon 1 (p.A20RfsX45) was identified; in family 4, a homozygous nonsense mutation in exon 3 (p.R153X) was identified; and in family 6, a 2 bp deletion at the end of exon 10 resulting in a frameshift (p.N489PfsX126) was identified. Pedigree of family 5 and agarose gel reveal no amplification of exon 3 in the affected individual. M represents the 100 bp DNA ladder, + represents the positive control, and – represents the negative control. All individuals screened are indicated by ∗, filled-in symbols represent affected individuals, and symbols containing a dot indicate heterozygote. The American Journal of Human Genetics 2010 86, 963-969DOI: (10.1016/j.ajhg.2010.05.006) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Protein Structure of Heparanase 2 Model of the predicted 50 kDa subunit of human heparanase 2 (residues 195–592) based on the crystal structure of the family 51 α-L-arabinofuranosidase13 (Protein Data Bank code 1PZ2). The part of the structure that is encoded by exons 8 and 9 is shown in marine blue. The N and C termini are indicated. This figure was prepared with the program PyMOL (DeLano Scientific LLC). The American Journal of Human Genetics 2010 86, 963-969DOI: (10.1016/j.ajhg.2010.05.006) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Expression of HPSE2 in Human and Murine Tissues (A) RT-PCR demonstrating expression of HPSE2 in embryonic brain tissue at Carnegie stages 16 and 21. (B) Direct in situ RT-PCR detection of HPSE2 mRNA expression human bladder tissue. Strong brown staining demonstrates expression in longitudinal smooth muscle tissue. (C) RT-PCR demonstrating expression of Hpse2 in E15 and adult mouse bladder, brain, kidney, and ureter. Hpse1 expression at E15 in the murine bladder, kidney, and ureter are positive, with no expression in the brain. In adult mouse tissue, Hpse1 is expressed in the bladder, but not in the brain. Hpse1 expression in the adult kidney is positive, but very weak, and the ureter is negative. The American Journal of Human Genetics 2010 86, 963-969DOI: (10.1016/j.ajhg.2010.05.006) Copyright © 2010 The American Society of Human Genetics Terms and Conditions