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The Clinical and Mutational Spectrum of B3GAT3 Linkeropathy

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The Clinical and Mutational Spectrum of B3GAT3 Linkeropathy Colman et al. Orphanet Journal of Rare Diseases (2019) 14:138 https://doi.org/10.1186/s13023-019-1110-9 RESEARCH Open Access The clinical and mutational spectrum of B3GAT3 linkeropathy: two case reports and literature review Marlies Colman1, Tim Van Damme1, Elisabeth Steichen-Gersdorf2, Franco Laccone3, Sheela Nampoothiri4, Delfien Syx1, Brecht Guillemyn1, Sofie Symoens1 and Fransiska Malfait1* Abstract Background: Proteoglycans are large and structurally complex macromolecules which can be found in abundancy in the extracellular matrix and on the surface of all animal cells. Mutations in the genes encoding the enzymes responsible for the formation of the tetrasaccharide linker region between the proteoglycan core protein and the glycosaminoglycan side chains lead to a spectrum of severe and overlapping autosomal recessive connective tissue disorders, collectively coined the ‘glycosaminoglycan linkeropathies’. Results: We report the clinical findings of two novel patients with a complex linkeropathy due to biallelic mutations in B3GAT3, the gene that encodes glucuronosyltransferase I, which catalyzes the addition of the ultimate saccharide to the linker region. We identified a previously reported c.667G > A missense mutation and an unreported homozygous c.416C > T missense mutation. We also performed a genotype and phenotype-oriented literature overview of all hitherto reported patients harbouring B3GAT3 mutations. A total of 23 patients from 10 families harbouring bi-allelic mutations and one patient with a heterozygeous splice-site mutation in B3GAT3 have been reported. They all display a complex phenotype characterized by consistent presence of skeletal dysplasia (including short stature, kyphosis, scoliosis and deformity of the long bones), facial dysmorphology, and spatulate distal phalanges. More variably present are cardiac defects, joint hypermobility, joint dislocations/contractures and fractures. Seven different B3GAT3 mutations have been reported, and although the number of patients is still limited, some phenotype-genotype correlations start to emerge. The more severe phenotypes seem to have mutations located in the substrate acceptor subdomain of the catalytic domain of the glucuronosyltransferase I protein while more mildly affected phenotypes seem to have mutations in the NTP-sugar donor substrate binding subdomain. Conclusions: Loss-of-function mutations in B3GAT3 are associated with a complex connective tissue phenotype characterized by disproportionate short stature, skeletal dysplasia, facial dysmorphism, spatulate distal phalanges and -to a lesser extent- joint contractures, joint hypermobility with dislocations, cardiac defects and bone fragility. Based on the limited number of reported patients, some genotype-phenotype correlations start to emerge. Keywords: Connective tissue, Glycosaminoglycans, GAG Linkeropathies, B3GAT3, Genotype, Phenotype * Correspondence: [email protected] 1Center for Medical Genetics, Ghent University and Ghent University Hospital, 0K5, Corneel Heymanslaan 10, B-9000 Ghent, Belgium Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Colman et al. Orphanet Journal of Rare Diseases (2019) 14:138 Page 2 of 10 Background B3GALT6-spEDS with cardiac defects, cervical spine in- Proteoglycans (PG) are large and structurally complex mac- stability, respiratory insufficiency and cerebrovascular acci- romolecules which can be found in abundancy in the extra- dents. Baasanjav et al. [32] reported the first biallelic cellular matrix and on the surface of all animal cells. PG are B3GAT3 mutations in a consanguineous family and hith- involved in a wide variety of functions such as cell-cell erto, B3GAT3 mutations have been reported in 24 patients communication, cell-matrix interactions and cell growth from 11 families, all displaying multisystemic conditions and differentiation. PGs consist of a core protein with one characterized by craniofacial, cardiovascular and skeletal or multiple glycosaminoglycan (GAG) sidechains covalently abnormalities [32–39]. attached to it. GAGs are composed of repeating disaccha- Here, we report the clinical and molecular findings in rides consisting of an amino sugar (N-acetylglucosamine two new independent patients with biallelic B3GAT3 [GlcNAc] or N-acetylgalactosamine [GalNAc]) and an ur- mutations and we provide a literature overview of the onic acid (glucuronic [GlcA] or iduronic acid [IdoA]). The genetic and phenotypic findings in all hitherto reported PG superfamily is subdivided into two major groups: hepa- B3GAT3 patients. We also performed structural model- ran sulfate (HS) and chondroitin sulfate (CS)/dermatan sul- ling of the reported missense mutations in B3GAT3 to fate (DS) PGs [1–3]. Before the polymerization of these HS investigate possible genotype-phenotype correlations. and CS/DS chains, the synthesis of a linker region consist- Our findings contribute to a better knowledge on the ing of four saccharides is obligatory. This is a stepwise genotypic and phenotypic spectrum of B3GAT3-related process requiring the coordinated action of specific trans- disease and its delineation from the other linkeropathies. ferases. First, a xylose unit is transferred onto a serine resi- due of the core protein by xylosyltransferase s I/II (encoded Results by XYLT1 and XYLT2), followed by the addition of two gal- Review of literature actose units by galactosyltransferase I (β4GalT7, encoded Mutations in B3GAT3 are extremely rare, with only 23 re- by B4GALT7) and galactosyltransferase II (β3GalT6, ported patients from 10 families harboring biallelic encoded by B3GALT6), respectively. The formation of the B3GAT3 mutations and one patient with a heterozygous linker region is completed by the transfer of glucuronic acid B3GAT3 mutation [32–39]. Consistent clinical findings in catalysed by glucuronosyltransferase I (GlcAT-I, encoded patients with biallelic B3GAT3 mutations are: skeletal dys- by B3GAT3)[4–9]. plasia (present in all) with shortening and bowing of long Biallelic mutations in all genes encoding these linker re- bones, (kypho)scoliosis, foot deformity and radioulnar syn- gion enzymes have been identified, leading to a spectrum of ostosis; disproportionate short stature (16/21, mentioned in overlapping autosomal recessive multisystemic disorders, 21 of 23 the cases); spatulate distal phalanges (14/15), and the ‘GAG linkeropathies’ [10]. Mutations in XYLT1 were re- facial dysmorphism, present in all patients, albeit with some ported in patients with short stature, intellectual disability, variability. Characteristic craniofacial features include ab- flat face and subsequently, XYLT1 mutations were identified normalities in cephalic index (brachycephaly and dolicho- in patients with Desbuquois dysplasia type 2 (OMIM cephaly), frontal bossing, hypertelorism, prominent eyes, #615777) [11–16]. Deficiency of XYLT2 causes a spondylo- downslanting palpebral fissures, midface hypoplasia, de- ocular syndrome (OMIM #605822) with eye and heart de- pressed nasal bridge, microstomia and short neck. Two in- fects, hearing loss, fractures and learning problems [17–22]. dividuals presented with blue sclerae. Common findings, B4GALT7 mutations are associated with a rare subtype of present in many but not all patients (> 60%), include dislo- the Ehlers-Danlos syndrome (EDS), spondylodysplastic cations of large joints (17/23), contractures of mostly the EDS (B4GALT7-spEDS; OMIM #130070), characterized by elbow joint (10/15) and structural cardiac defects, including short stature, joint hypermobility, hyperelastic skin, osteo- septal defects and valve abnormalities (12/18). A number of penia and ocular problems [23–28]. A specific homozygous features is more variably present (< 60%). Multiple fractures B4GALT7 mutation,c.808C>Tp.(Arg270Cys),isassoci- were reported in 7 patients and joint hypermobility was ated with the Larsen of Reunion Island syndrome, charac- noted in 8 individuals. Skin involvement is uncommon, terized by severe joint hypermobility with dislocations [29]. with hyperextensible skin, cutis laxa and excessive wrink- Biallelic mutations in B3GALT6alsocauseaspectrumof ling on the palms of the hands, each reported only once overlapping disorders. Malfait et al. [30] described a sub- [33, 36, 38]. Ocular problems are rare (only present in 3 pa- type of EDS (spondylodysplastic EDS, B3GALT6-spEDS) tients) and diverse, including glaucoma, hyperopia, esotro- with skin fragility, delayed wound healing, joint laxity/con- pia, amblyopia and astigmatism [36–38]. Intellectual tractures, intellectual disability and spondyloepimetaphyseal disability was noted in 2 patients, one of which had mul- dysplasia, whereas Nakajima et al. [10] described a group of tiple brain infarctions and subdural hematomas [37]. Since individuals suffering from spondyloepimetaphyseal dyspla- at least 9 of the families are consanguineous, some rare fea- sia with joint
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