Deletion and Point Mutations of PTHLH Cause Brachydactyly Type E

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Deletion and Point Mutations of PTHLH Cause Brachydactyly Type E Eva Klopocki, Bianca P. Hennig, Katarina Dathe, Randi Koll, Thomy de Ravel, Emiel Baten, Eveline Blom, Yves Gillerot, Johannes F.W. Weigel, Gabriele Krüger, Olaf Hiort, Petra Seemann, Stefan Mundlos The American Journal of Human Genetics Volume 86, Issue 3, Pages 434-439 (March 2010) DOI: 10.1016/j.ajhg.2010.01.023 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of Families 1–5 Affected individuals are indicated by black symbols. Symbols with crossed lines indicate individuals of whom material was available for testing, and stars indicate individuals of whom clinical or X-ray images are shown in Figure 2. The American Journal of Human Genetics 2010 86, 434-439DOI: (10.1016/j.ajhg.2010.01.023) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical Phenotypes (A–D) Family 1, IV-3 (large deletion). Note severe BDE phenotype with small hands (A and C) and feet (B and D) due to shortening of all metacarpals and second to fifth metatarsals (arrows on X-rays). Note additional shortened middle phalanx of digits II and V (A, stars). (E and F) Family 2, II-1 (missense mutation L60P). Note small hands with shortened third to fifth metacarpals. Middle and distal phalanges of index and fifth finger are short (E, stars). (G) Family 3, II-1 (missense mutation L44P). Besides shortened metacarpals III–V, note cone-shaped epiphyses at the phalanges (arrows) and premature closure of the metacarpal epiphyses at the age of 9 years. Epiphyses of ulnar and radius appear irregular and flattened. (H) Family 4, III-1 (nonstop mutation). Note shortened third and fifth metacarpals and abnormal epiphyses prematurely fused to their metaphyses (arrow). (I) Growth chart of female individuals from family 1 (IV-15) and family 2 (II-1). Note that growth velocity of affected individuals stops prematurely, resulting in small stature. The American Journal of Human Genetics 2010 86, 434-439DOI: (10.1016/j.ajhg.2010.01.023) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutations Associated with BDE An ∼907 kb genomic microdeletion on chromosome 12p was detected in family 1 affecting six genes (gray bar, top; ISCN2009: array 12p11.23p11.22(27,341,677-28,249,358)x1). Point mutations within the PTHLH gene observed in families 2–5 are indicated (bottom). Genes are shown as dark gray boxes, with transcriptional orientation indicated by arrow heads. Small arrows point to genomic position of qPCR amplicons. Exon structure of PTHLH gene is according to NM_198966. Location of the start codon (ATG) in exon 2 is indicated. Genomic positions are according to hg18. Top: 1 mm represents 5 kb. Bottom: exons, 1 mm represents 10 bp; introns, 1 mm represents 100 bp. The American Journal of Human Genetics 2010 86, 434-439DOI: (10.1016/j.ajhg.2010.01.023) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Functional Testing of Missense Mutation L60P in Chicken Micromass System WT Pthlh (B and F) and L60P mutant (C and H) were retrovirally overexpressed in micromass cultures from chicken limb buds and were grown for 7 days (A–C) and 10 days (D–F) in culture medium. In comparison to the WT, the L60P mutant does not show a strong suppression of ALP activity (D and H). However, ALP activity is reduced compared to the uninfected control (D and H). The American Journal of Human Genetics 2010 86, 434-439DOI: (10.1016/j.ajhg.2010.01.023) Copyright © 2010 The American Society of Human Genetics Terms and Conditions