Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome.
Ehlers-Danlos syndrome (EDS) is a heterogeneous connective tissue disorder involving skin and joint laxity and tissue fragility. A new type of EDS, similar to kyphoscoliosis type but without lysyl hydroxylase deficiency, has been investigated. We have identified a homozygous CHST14 (carbohydrate sulfotransferase 14) mutation in the two familial cases and compound heterozygous mutations in four sporadic cases. CHST14 encodes dermatan 4-O-sulfotransferase 1 (D4ST1), which transfers active sulfate from 3'-phosphoadenosine 5'-phosphosulfate to position 4 of the N-acetyl-D-galactosamine (GalNAc) residues of dermatan sulfate (DS). Transfection experiments of mutants and enzyme assays using fibroblast lysates of patients showed the loss of D4ST1 activity. CHST14 mutations altered the glycosaminoglycan (GAG) components in patients' fibroblasts. Interestingly, DS of decorin proteoglycan, a key regulator of collagen fibril assembly, was completely lost and replaced by chondroitin sulfate (CS) in the patients' fibroblasts, leading to decreased flexibility of GAG chains. The loss of the decorin DS proteoglycan due to CHST14 mutations may preclude proper collagen bundle formation or maintenance of collagen bundles while the sizes and shapes of collagen fibrils are unchanged as observed in the patients' dermal tissues. These findings indicate the important role of decorin DS in the extracellular matrix and a novel pathomechanism in EDS.
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. nmiyake@yokohama-cu.ac.jp
Noriko
N
Miyake
Tomoki
T
Kosho
Shuji
S
Mizumoto
Tatsuya
T
Furuichi
Atsushi
A
Hatamochi
Yoji
Y
Nagashima
Eiichi
E
Arai
Kazuo
K
Takahashi
Rie
R
Kawamura
Keiko
K
Wakui
Jun
J
Takahashi
Hiroyuki
H
Kato
Hiroshi
H
Yasui
Tadao
T
Ishida
Hirofumi
H
Ohashi
Gen
G
Nishimura
Masaaki
M
Shiina
Hirotomo
H
Saitsu
Yoshinori
Y
Tsurusaki
Hiroshi
H
Doi
Yoshimitsu
Y
Fukushima
Shiro
S
Ikegawa
Shuhei
S
Yamada
Kazuyuki
K
Sugahara
Naomichi
N
Matsumoto
D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D003094:Collagen / Q000378:metabolism; D058575:Decorin; D020405:Dermis / Q000473:pathology; D004535:Ehlers-Danlos Syndrome / Q000145:classification* / Q000201:enzymology / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011509:Proteoglycans / Q000378:metabolism; D015398:Signal Transduction; D015238:Sulfotransferases / Q000737:chemistry / Q000235:genetics*; D016212:Transforming Growth Factor beta; D000097811:Carbohydrate Sulfotransferases
D003094:Collagen; D058575:Decorin; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D011509:Proteoglycans; D015238:Sulfotransferases; D016212:Transforming Growth Factor beta; D000097811:Carbohydrate Sulfotransferases; C546878:DCN protein, human