Autosomal recessive stickler syndrome due to a loss of function mutation in the COL9A3 gene

Abstract

Stickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis.

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

“…To date, multiple mutations in the collagen-encoding genes COL2A1 , COL11A1 , COL11A2 , COL9A1 , COL9A2 , and COL9A3 have been associated with six genetically distinct types of Stickler syndrome [15,98,99,100,101,102,103]. Types I-III, resulting from mutations in COL2A1 , COL11A1 , and COL11A2 , are inherited in an autosomal dominant manner and account for the majority of occurrences of the disorder.…”

Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation

“…Four families have been described with autosomal recessive Stickler syndrome due to mutations in the COL11A1 type XI procollagen gene (Alzahrani, Alshammari, & Alkuraya, ; Richards et al, ). Five families have been described with autosomal recessive Stickler syndrome due to homozygosity for loss‐of‐function mutations in the COL9A1 and COL9A2 type IX procollagen genes (Baker et al, ; Nikopoulos et al, ; Van Camp et al, ) and, more recently, COL9A3 (Faletra et al, ).…”

Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing

“…Third, the involvement of other, perhaps still unidentified genes for Stickler syndrome cannot be excluded. Mutations in the genes encoding type IX collagen have been identified in a few families exhibiting an autosomal recessive form of Stickler syndrome with clinical features partly distinct from the three main Stickler types [31][32][33]. Moreover, considerable phenotypical overlap between Stickler syndrome and other connective tissue dysplasias, such as Marfan, Ehlers-Danlos and Loeys-Dietz syndrome, exists.…”