Mesomelia-Synostoses Syndrome Results from Deletion of SULF1 and SLCO5A1 Genes at 8q13

Abstract

Mesomelia-synostoses syndrome (MSS) or mesomelic dysplasia with acral synostoses Verloes-David-Pfeiffer type is a rare autosomal-dominant disorder characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations. So far, five patients in four unrelated families have been reported worldwide with MMS. By using whole-genome oligonucleotide array CGH, we have identified an interstitial deletion at 8q13 in all patients. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1, encoding the heparan sulfate 6-O-endosulfatase 1, and SLCO5A1, encoding the solute carrier organic anion transporter family member 5A1. SULF1 acts as a regulator of numerous growth factors in skeletal embryonic development whereas the function of SLCO5A1 is yet unknown. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Real-time quantitative RT-PCR analysis showed the highest levels of SULF1 transcripts in human osteoblasts and cartilage whereas SLCO5A1 was highly expressed in human fetal and adult brain and heart. Our results strongly suggest that haploinsufficiency of SULF1 contributes to this mesomelic chondrodysplasia, highlighting the critical role of endosulfatase in human skeletal development. Codeletion of SULF1 and SLCO5A1--which does not result from a low-copy repeats (LCRs)-mediated recombination event in at least two families--was found in all patients, so we suggest that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS.

The Role of Drosophila Heparan Sulfate 6-O-Endosulfatase in Sulfation Compensation*

“…After HSPGs are transported to the cell surface, HS structure can be further modulated by extracellular HS 6-O-endosulfatases (Sulfs), which remove a specific subset of 6-O-sulfate groups within the highly sulfated domains on HS (7)(8)(9)(10)(11)(12). In humans, mutations in Sulfs are associated with tumorigenesis (13,14) and with Mesomelia-Synostoses syndrome, an autosomal dominant human disorder characterized by limb shortening, acral synostoses, and multiple congenital malformations (15). These Golgi and extracellular enzymes regulate the amount and pattern of sulfate groups on HS, which play critical roles in creating binding sites on HS for a variety of ligand proteins (16,17).…”

Genetics and pathophysiology of mammalian sulfate biology

“…The human SULF1 gene has been linked to mesomelia-synostoses syndrome that has clinical features of limb shortening and acral synostoses (Isidor et al, 2010). Similar developmental defects are observed in Sulf1 and Sulf2 null mice (Holst et al, 2007).…”

Recurrent 8q13.2-13.3 microdeletions associated with Branchio-oto-renal syndrome are mediated by human endogenous retroviral (HERV) sequence blocks

“…MSS is a rare dominantly inherited disorder characterized by mesomelic limb shortening and acral synostoses, renal malformations and/or congenital heart defects occur sporadically. Hearing loss has not been reported in MSS patients [30,31], although <10 patients with MSS have been described [29,32]. We summarized the clinical phenotypes of reported carriers with 8q13.2-13.3 microdeletion carriers reported in the literatures (Table 1) [22,26].…”

“…The typical manifestations of BOR are hearing loss and structural defects of the outer, middle, and inner ear (98.5%), preauricular pits (83.6%), branchial anomalies (68.5%), renal anomalies (38.2%), and external ear abnormalities (31.5%) [11]. 8q13 has also reportedly been associated with Mesomelia-Synostoses syndrome (MSS, OMIM 600383) due to the co-deletion of SULF1 and SLCO5A1 [29]. MSS is a rare dominantly inherited disorder characterized by mesomelic limb shortening and acral synostoses, renal malformations and/or congenital heart defects occur sporadically.…”