| Author |
Shuji Mizumoto, Tomoki Kosho, Tomoko Honda, Atsushi Hatamochi, Kazuyuki Sugahara, Naomichi Matsumoto, Noriko Miyake, Shuhei Yamada
|
| Abstract |
ABSTRACT
Musculocontractural Ehlers‐Danlos syndrome (EDS) caused by pathogenic variants in the carbohydrate sulfotransferase 14 gene (
CHST14
) (mcEDS‐
CHST14
) is an autosomal recessive connective tissue disorder characterized by congenital malformations including specific craniofacial features, congenital multiple contractures, and progressive fragility‐related complications.
CHST14
encodes dermatan 4‐
O
‐sulfotransferase‐1 (D4ST1), which is responsible for the biosynthesis of dermatan sulfate (DS). DS plays a number of roles in a wide range of biological activities such as cell signaling and tissue morphogenesis through interactions with various growth factors and extracellular matrix proteins. A nonsense variant and four missense variants of
CHST14
in patients with mcEDS‐
CHST14
were found to show a decreased sulfotransferase activity [Miyake et al., Hum. Mutat. 31, 966–974, 2010]. However, it remains unclear how an atypical pathogenic variant in the initiation codon of
CHST14
affects the enzymatic activity as well as subcellular localization. To characterize an atypical variant, a 9‐bp deletion affecting the initiation methionine codon in
CHST14
(NM_130468.3:c.2_10del:p.M1_R4del), glycobiological analyses were performed. Sulfotransferase activity from the cultured skin fibroblasts of a patient and cellular localization of the mutant D4ST1 were examined. DS from urine and fibroblasts of the patient were quantified by anion‐exchange chromatography. The mutant enzyme showed a lower molecular weight compared with the wild‐type, indicating that another ATG in the coding region of
CHST14
might function in translation initiation. Furthermore, the wild‐type D4ST1 was localized in Golgi apparatus, whereas mutant D4ST1 was observed in the cytoplasm and nucleus, which may be functionally null due to the mislocalization in addition to a considerably decrease in sulfotransferase activity. DS was defective in fibroblasts as well as urine of the patient. This is the first study to examine glycobiological characterization of a variant affecting the initiation codon of
CHST14
in mcEDS‐
CHST14
. The truncated D4ST1 protein was estimated to exert a complete loss of function, through mislocalization of the protein in the cytoplasm and nucleus, which resulted in mcEDS‐
CHST14
.
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