Identification of biallelic EXTL3 mutations in a novel type of spondylo-epi-metaphyseal dysplasia.
Spondylo-epi-metaphyseal dysplasia (SEMD) is a group of inherited skeletal diseases characterized by the anomalies in spine, epiphyses and metaphyses. SEMD is highly heterogeneous and >20 distinct entities have been identified. Here we describe a novel type of SEMD in two unrelated Turkish patients who presented with severe platyspondyly, kyphoscoliosis, pelvic distortion, constriction of the proximal femora and brachydactyly. Although these phenotypes overlap considerably with some known SEMDs, they had a novel causal gene, exostosin-like glycosyltransferase 3 (EXTL3), that encodes a glycosyltransferase involved in the synthesis of heparin and heparan sulfate. The EXTL3 mutation identified in the patients was a homozygous missense mutation (c.953C>T) that caused a substitution in a highly conserved amino acid (p.P318L). The enzyme activity of the mutant EXTL3 protein was significantly decreased compared to the wild-type protein. Both patients had spinal cord compression at the cranio-vertebral junction and multiple liver cysts since early infancy. One of the patients showed severe immunodeficiency, which is considered non-fortuitous association. Our findings would help define a novel type of SEMD caused by EXTL3 mutations.
Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
Long
L
Guo
Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey.|Eastern Mediterranean University Medical School, Cyprus, Mersin, Turkey.
Nursel H
NH
Elcioglu
Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Shuji
S
Mizumoto
Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
Zheng
Z
Wang
Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey.
Bilge
B
Noyan
Department of Pediatric Genetics, Ondokuz Mayis University Medical School, Samsun, Turkey.
Hatice M
HM
Albayrak
Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Shuhei
S
Yamada
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Naomichi
N
Matsumoto
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Noriko
N
Miyake
Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.|Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan.
Gen
G
Nishimura
Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
Shiro
S
Ikegawa
D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010641:Phenotype
C110774:EXTL3 protein, human; D017351:N-Acetylglucosaminyltransferases