2. Academic Validation
  3. Homozygosity for frameshift mutations in XYLT2 result in a spondylo-ocular syndrome with bone fragility, cataracts, and hearing defects

Homozygosity for frameshift mutations in XYLT2 result in a spondylo-ocular syndrome with bone fragility, cataracts, and hearing defects

  • Am J Hum Genet. 2015 Jun 4;96(6):971-8. doi: 10.1016/j.ajhg.2015.04.017.
Craig F Munns 1,  Somayyeh Fahiminiya 2,  Nabin Poudel 3,  Maria Cristina Munteanu 3,  Jacek Majewski 2,  David O Sillence 4,  Jordan P Metcalf 5,  Andrew Biggin 1,  Francis Glorieux 6,  François Fassier 6,  Frank Rauch 6,  Myron E Hinsdale 7
Affiliations

Affiliations

  • 1 Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
  • 2 Department of Human Genetics, Faculty of Medicine, McGill University and Genome Quebec Innovation Center, Montréal, QC H3A 1B1, Canada.
  • 3 Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
  • 4 Discipline of Genetic Medicine, The Children's Hospital at Westmead Clinical School, Sydney Medicine, Westmead, NSW 2145, Australia.
  • 5 Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA.
  • 6 Shriners Hospital for Children, Montréal, QC H3G 1A6, Canada.
  • 7 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: [email protected].
PMID: 26027496 DOI: 10.1016/j.ajhg.2015.04.017
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.

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