Homozygous Mutations in ADAMTS10 and ADAMTS17 Cause Lenticular Myopia, Ectopia Lentis, Glaucoma, Spherophakia, and Short Stature

Abstract

Weill-Marchesani syndrome (WMS) is a well-characterized disorder in which patients develop eye and skeletal abnormalities. Autosomal-recessive and autosomal-dominant forms of WMS are caused by mutations in ADAMTS10 and FBN1 genes, respectively. Here we report on 13 patients from seven unrelated families from the Arabian Peninsula. These patients have a constellation of features that fall within the WMS spectrum and follow an autosomal-recessive mode of inheritance. Individuals who came from two families and met the diagnostic criteria for WMS were each found to have a different homozygous missense mutation in ADAMTS10. Linkage analysis and direct sequencing of candidate genes in another two families and a sporadic case with phenotypes best described as WMS-like led to the identification of three homozygous mutations in the closely related ADAMTS17 gene. Our clinical and genetic findings suggest that ADAMTS17 plays a role in crystalline lens zonules and connective tissue formation and that mutations in ADAMTS17 are sufficient to produce some of the main features typically described in WMS.

Copy number variants in patients with short stature

“…GH secretion and circulating IGF-I were normal, but IGFBP-3 was low ( À2 SDS). Several arguments are in favor of a role of ADAMTS17 in growth regulation (for summary, see Table 3), including: (1) significant association with height in population GWAS; 1 (2) a short child with a similar terminal deletion in the DECIPHER database; (3) significant association with size in a GWAS in the domestic dog; 29 (4) human mutations in ADAMTS17 causing the acromelic chondrodysplasia Weill-Marchesani-like syndrome (OMIM #277600 and #608328); [30][31][32][33] and (5) association of members of the ADAMTSL/ADAMTS family with the modulation of fibrillin-1 function. 31,33 Unfortunately, expression of the rodent homolog of ADAMTS17 could not be investigated, because the gene was not represented on the microarrays used.…”

“…39 Case II.17, described previously, 12 carries a duplication of 3p12.3 containing part of ROBO2, encoding a receptor for SLIT2 and probably SLIT1, thought to function in axon guidance and cell migration. 40 Case II.21, born SGA, length À3.7 SDS and head circumference À3.1 SDS presented with clinodactily, a protruded [30][31][32][33] Associated with fibrillin-1 function. 31,33 Aldh1a3 and Lrrk1 higher expressed in murine GP; Chsy1 highly expressed in HZ and downregulated with age.…”

Molecular pathogenesis and management strategies of ectopia lentis

“…EL is described in the majority of both dominant and recessive cases. 49 In 2009, Morales and colleagues 47 described homozygous mutations in ADAMTS17 on 15q24 in a consanguineous family causing EL and short stature. This family did not fulfil the diagnosis of WMS.…”

Changes of the Expressions of Orphan and gon- ADAMTS in Chondrosarcoma Cells

“…Mutation in ADAMTS17 is associated with Weil-Marchesani syndrome like ADAMTS10. 40,41 Our study is the first study to investigate relations of cancer and ADAMTS17 as well. According to our findings, ADAMTS17 levels were increased after insulin application in chondrosarcoma.…”