Temtamy Preaxial Brachydactyly Syndrome Is Caused by Loss-of-Function Mutations in Chondroitin Synthase 1, a Potential Target of BMP Signaling

Abstract

Altered Bone Morphogenetic Protein (BMP) signaling leads to multiple developmental defects, including brachydactyly and deafness. Here we identify chondroitin synthase 1 (CHSY1) as a potential mediator of BMP effects. We show that loss of human CHSY1 function causes autosomal-recessive Temtamy preaxial brachydactyly syndrome (TPBS), mainly characterized by limb malformations, short stature, and hearing loss. After mapping the TPBS locus to chromosome 15q26-qterm, we identified causative mutations in five consanguineous TPBS families. In zebrafish, antisense-mediated chsy1 knockdown causes defects in multiple developmental processes, some of which are likely to also be causative in the etiology of TPBS. In the inner ears of zebrafish larvae, chsy1 is expressed similarly to the BMP inhibitor dan and in a complementary fashion to bmp2b. Furthermore, unrestricted Bmp2b signaling or loss of Dan activity leads to reduced chsy1 expression and, during epithelial morphogenesis, defects similar to those that occur upon Chsy1 inactivation, indicating that Bmp signaling affects inner-ear development by repressing chsy1. In addition, we obtained strikingly similar zebrafish phenotypes after chsy1 overexpression, which might explain why, in humans, brachydactyly can be caused by mutations leading either to loss or to gain of BMP signaling.

Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in theERFgene

“…Desbuquois syndrome is associated with hyperphalangism and joint dislocations (OMIM #251450 and #615777) and is caused by mutations in the CANT1 and XYLT1 genes 8 9. Temtamy hyperphalangism (OMIM #605282) was reported to be caused by mutations in the CHSY1 gene 10 11. These hyperphalangy genes encode enzymes that appear to be involved in proteoglycan synthesis or sulfation.…”

Two different Temtamy syndromes

“…The association of hyperphalangism with mental retardation occurs in Temtamy preaxial brachydactyly syndrome first identified by Temtamy et al (1998) and the gene mutation responsible (chondroitin synthase 1, CHSY1) was identified by Li et al (2010). Because of the variable phenotype observed by Temtamy et al (2012) in the 16 reported cases, I recommend that Dias et al (2012) have their patient tested for the CHSY1 mutation.…”

Diseases of glycosylation beyond classical congenital disorders of glycosylation

“…5). Most CHSY1 mutations identified in patients with Temtamy preaxial brachydactyly syndrome are deletions leading to truncated proteins and probably complete loss of enzymatic activity [77]. The clinical picture of the syndrome is characterized by a form of digit malformation called preaxial brachydactyly but also by mental and growth retardation, facial dysmorphism and hearing loss.…”

“…The second disease of GAG chain polymerization is called Temtamy preaxial brachydactyly syndrome [77], which is caused by mutations in the chondroitin synthase-1 gene (CHSY1, OMIM ID: 608183).…”