title: Homozygosity for frameshift mutations in XYLT2 result in a spondylo-ocular syndrome with bone fragility, cataracts, and hearing defects.
abstract: Heparan and chondroitin/dermatan sulfated proteoglycans have a wide range of roles in cellular and tissue homeostasis including growth factor function, morphogen gradient formation, and co-receptor activity. Proteoglycan assembly initiates with a xylose monosaccharide covalently attached by either xylosyltransferase I or II. Three individuals from two families were found that exhibited similar phenotypes. The index case subjects were two brothers, individuals 1 and 2, who presented with osteoporosis, cataracts, sensorineural hearing loss, and mild learning defects. Whole exome sequence analyses showed that both individuals had a homozygous c.692dup mutation (GenBank: NM_022167.3) in the xylosyltransferase II locus (XYLT2) (MIM: 608125), causing reduced XYLT2 mRNA and low circulating xylosyltransferase (XylT) activity. In an unrelated boy (individual 3) from the second family, we noted low serum XylT activity. Sanger sequencing of XYLT2 in this individual revealed a c.520del mutation in exon 2 that resulted in a frameshift and premature stop codon (p.Ala174Profs(∗)35). Fibroblasts from individuals 1 and 2 showed a range of defects including reduced XylT activity, GAG incorporation of (35)SO4, and heparan sulfate proteoglycan assembly. These studies demonstrate that human XylT2 deficiency results in vertebral compression fractures, sensorineural hearing loss, eye defects, and heart defects, a phenotype that is similar to the autosomal-recessive disorder spondylo-ocular syndrome of unknown cause. This phenotype is different from what has been reported in individuals with other linker enzyme deficiencies. These studies illustrate that the cells of the lens, retina, heart muscle, inner ear, and bone are dependent on XylT2 for proteoglycan assembly in humans.
authors.affiliation: Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
authors.forename: Craig F
authors.initials: CF
authors.lastname: Munns
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University and Genome Quebec Innovation Center, Montréal, QC H3A 1B1, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Nabin
authors.initials: N
authors.lastname: Poudel
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Munteanu
authors.affiliation: Department of Human Genetics, Faculty of Medicine, McGill University and Genome Quebec Innovation Center, Montréal, QC H3A 1B1, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Discipline of Genetic Medicine, The Children's Hospital at Westmead Clinical School, Sydney Medicine, Westmead, NSW 2145, Australia.
authors.forename: David O
authors.initials: DO
authors.lastname: Sillence
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA.
authors.forename: Jordan P
authors.initials: JP
authors.lastname: Metcalf
authors.affiliation: Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Biggin
authors.affiliation: Shriners Hospital for Children, Montréal, QC H3G 1A6, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Glorieux
authors.affiliation: Shriners Hospital for Children, Montréal, QC H3G 1A6, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Fassier
authors.affiliation: Shriners Hospital for Children, Montréal, QC H3G 1A6, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Rauch
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA. Electronic address: myron.hinsdale@okstate.edu.
authors.forename: Myron E
authors.initials: ME
authors.lastname: Hinsdale
mesh_terms: D001483:Base Sequence; D002386:Cataract / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D019465:Craniofacial Abnormalities / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D004164:Diphosphonates / Q000627:therapeutic use; D059472:Exome / Q000235:genetics; D015785:Eye Diseases, Hereditary / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D016368:Frameshift Mutation / Q000235:genetics*; D006311:Hearing Disorders / Q000235:genetics / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D010009:Osteochondrodysplasias / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000235:genetics; D000077268:Pamidronate; D010375:Pedigree; D010430:Pentosyltransferases / Q000097:blood / Q000235:genetics*; D011859:Radiography; D060888:Real-Time Polymerase Chain Reaction; D012163:Retinal Detachment / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D017422:Sequence Analysis, DNA; D000097608:UDP Xylose-Protein Xylosyltransferase
chemical_list: D004164:Diphosphonates; D000077268:Pamidronate; D010430:Pentosyltransferases; D000097608:UDP Xylose-Protein Xylosyltransferase