Background Mutations within the C-terminal region of the COL6A1 gene are

Background Mutations within the C-terminal region of the COL6A1 gene are only detected in Ullrich/Bethlem patients on extremely rare occasions. a central triple-helix (TH) domain name with repeating Gly-Xaa-Yaa sequences flanked by N- and C-globular domains [4-6]. Formation of collagen VI is usually a complex multi-step process: inside the cells, the equimolar association of the three subunits to form a triple-helical monomer is usually followed by assembly into disulphide-bonded anti-parallel dimers, which then align to form tetramers, also stabilized by disulphide bonds. Outside the cell, the tetramers, the secreted form of collagen VI, associate end-to-end through overlapping N-terminal globular domains, thereby forming double-beaded microfibrils [1]. Mutations in the genes cause collagen VI-related myopathies, a group of allelic disorders exhibiting a variable combination of muscle mass losing and weakness, joint contractures, distal laxity, and respiratory compromise [7-9]. Ullrich congenital muscular dystrophy (UCMD, OMIM #254090), caused by both inherited recessive and dominant COL6 mutations, is the most severe of these disorders. In UCMD patients, collagen VI is typically reduced or absent in the muscle mass and in cultured AZD5438 skin fibroblasts [10-12]. The majority of COL6 gene mutations reported in UCMD patients result in premature termination codons [7,8; Leiden Muscular Dystrophy pages,, and]. In addition, missense mutations substituting glycine in the TH Gly-Xaa-Yaa motif are frequently reported [7,8,13], as well as splicing mutations leading to in-frame exon deletions [7,8,14]. Although obvious mutational hot spots have not been recognized, exon 10 of COL6A1, exon 26 of COL6A2 and intron 16 of COL6A3 seems to be preferentially mutated [8] and the topographical distribution of mutations along the different protein domains differs between AZD5438 the chains. In the 2 2(VI) chain, mutations have been explained affecting N-terminal, TH and C-terminal domains to a similar degree. In contrast, mutations in 1(VI) and 3(VI) chains are almost exclusively located in the TH and N-terminal domains, with just few in frame deletions and missense changes affecting the C-terminal regions AZD5438 have been explained and in general mutations in these C-domains being very rare [8; Leiden Muscular Dystrophy pages, and]. Indeed, no truncating mutations have been explained in this domain name of the 3(VI) chain, and only one case of UCMD transporting a homozygous Igf2r truncating mutation within the a1(VI) chain C-terminus has been reported [15]. In this study we characterize the clinical, transcriptional, immunohistochemical and biochemical features of a rare example of truncating mutations within the C-terminal domain name of the COL6A1 gene, detected in two Brazilian brothers with UCMD. Case presentation The two Brazilian brothers both have a clinical diagnosis of UCMD; they were given birth to from non-related parents, neither of whom reported a family history of neuromuscular diseases. The eldest individual was unable to walk autonomously until he was 3 years of age, whereupon he consistently showed a waddling gait, a severe difficulty in climbing stairs and rising from the floor, and a total inability to run. At the age of 5 he lost the ability to walk. Clinical examination at 9 years evidenced: severe muscle mass weakness, predominantly including proximal muscles, marked hyperlaxity of the skin and distal joints and contractures of the knees and elbows. Respiratory function and serum CK were normal, and no significant scoliosis was reported. The youngest sib has a comparable clinical presentation but, differently from your brother, he was by no means able to walk. At the age of examination (5 years), he was completely unable to lift his arms or legs against the pressure of gravity. He also displayed skin and joint hyperlaxity (Physique?1) and mild contractures of the hips and knees. Neither scoliosis nor respiratory problems were evident. Physique 1 Clinical presentation of the youngest sib: a) The patient is unable to lift his arms against the pressure of gravity; b) detail on hyperlaxity of fingers. Methods DNA and RNA analyses The study was approved by the local ethics committee (Comitato Etico Della Provincia di Ferrara). Genomic sequencing of COL6 genes was performed, as.