BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia

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BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia Sung Yoon Cho, Jun-Seok Bae, Nayoung K.D. Kim, Francesca Forzano, Katta Mohan Girisha, Chiara Baldo, Francesca Faravelli, Tae- Joon Cho, Dongsup Kim, Kyoung Yeul Lee, Shiro Ikegawa, Jong Sup Shim, Ah-Ra Ko, Noriko Miyake, Gen Nishimura, Andrea Superti- Furga, Jürgen Spranger, Ok-Hwa Kim, Woong-Yang Park, Dong-Kyu Jin The American Journal of Human Genetics Volume 98, Issue 6, Pages 1243-1248 (June 2016) DOI: 10.1016/j.ajhg.2016.04.004 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of Three Families Showing the Segregation of BGN Mutant Alleles Shown are the pedigrees of the Korean family (A), the Italian family (B), and the Indian individual (C). Open boxes represent healthy males, and open circles represent healthy females. Filled boxes represent affected males. Boxes or circles with a line across indicate that the person has died. All circles with a dot in the middle indicate the status of carrier. Alleles with the wild-type genotype are indicated by a plus sign. Samples were not available for individuals lacking a genotype designation. The American Journal of Human Genetics 2016 98, 1243-1248DOI: (10.1016/j.ajhg.2016.04.004) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Radiologic Characteristics of Individuals with XLR SEMD BGN Type (A) Korean family member IV-1’s radiographs at age 5 years. Spine lateral shows platyspondyly with beaking appearance of its anterocentral portion and accentuated lordotic spinal curve. Note brachymetacarpals and phalanges and delayed carpal bone ages. Metaphyseal flaring and cupping are noted at the distal radii and ulnae. Pelvis shows flared iliac wings with flat acetabuli. The femoral necks are constricted and elongated. Small and dysplastic capital femoral epiphyses are seen. Note marked metaphyseal flaring and cupping of the lower extremity. (B) Korean family member II-2, grandfather of IV-1, radiographs at age 70 years. Lateral spine shows platyspondyly and anterior wedging at L1 and L2 vertebral bodies, with kyphosis at the thoracolumbar spine. Hands show uniform brachydactyly, especially brachymetacarpals. Pelvis reveals flared iliac wings and constricted femoral necks. Hip joints are preserved for his age. Marked shortening of the femora, tibiae, and fibulae with metaphyseal widening are noted. Knee joints are intact. (C) Indian family 3, a simplex case, radiographs at 10 years of age. Lateral spine shows platyspondyly with residue of anterior beaking. Wedging is noted at L1 vertebral body. Pelvis shows flared iliac wings with flat and irregular acetabuli. Femoral necks are constricted and elongated, and dysplastic capital femoral epiphyses with lateral subluxation are seen. Metaphyseal flaring and cupping are noted at the distal femoral and proximal tibiae with impinging epiphyses within cupping metaphyses. Hands show uniformly short metacarpals and phalanges and markedly delayed bone age. The American Journal of Human Genetics 2016 98, 1243-1248DOI: (10.1016/j.ajhg.2016.04.004) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 Pathogenic Variant in BGN and Molecular Interactions between Biglycan and TGF-β (A) The schematic diagram of BGN and the position of two identified variants. The two BGN variants (c.439A>G [p.Lys147Glu] and c.776G>T [p.Gly259Val]) are located in the leucine-rich repeat (LRR) domain. The asterisk (∗) marks conserved amino acid residue in biglycan (BGN) and decorin (DCN). Boxed amino acid residues indicate conserved functional leucine in the LRR domain. (B) Structural change brought about two substitutions (p.Lys147Glu and p.Gly259Val) predicted by molecular dynamics simulation. Arrows at merged structures indicate the place where beta sheets at the biglycan (BGN) concave region are significantly perturbed by mutations. (C) Structural model of BGN (green) and TGF-β (blue) dimer. Red functional residues indicate the substituted sites (p.Lys147Glu). (D) Structure simulation models for BGN p.Lys147Glu with TGF-β in overall and interface close-up view. Yellow dotted lines in close-up view show polar interactions between functional groups around Glu147. Abbreviations are as follows: WT, wild-type biglycan; SUB, substituted biglycan. The American Journal of Human Genetics 2016 98, 1243-1248DOI: (10.1016/j.ajhg.2016.04.004) Copyright © 2016 American Society of Human Genetics Terms and Conditions