BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia

Abstract

Spondyloepimetaphyseal dysplasias (SEMDs) comprise a heterogeneous group of autosomal-dominant and autosomal-recessive disorders. An apparent X-linked recessive (XLR) form of SEMD in a single Italian family was previously reported. We have been able to restudy this family together with a second family from Korea by segregating a severe SEMD in an X-linked pattern. Exome sequencing showed missense mutations in BGN c.439A>G (p.Lys147Glu) in the Korean family and c.776G>T (p.Gly259Val) in the Italian family; the c.439A>G (p.Lys147Glu) mutation was also identified in a further simplex SEMD case from India. Biglycan is an extracellular matrix proteoglycan that can bind transforming growth factor beta (TGF-β) and thus regulate its free concentration. In 3-dimensional simulation, both altered residues localized to the concave arc of leucine-rich repeat domains of biglycan that interact with TGF-β. The observation of recurrent BGN mutations in XLR SEMD individuals from different ethnic backgrounds allows us to define "XLR SEMD, BGN type" as a nosologic entity.

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.

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.

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.