Abstract
TCAP encoded telethonin is a 19 kDa protein, which plays an important role in anchoring titin in Z disc of the sarcomere, and is known to cause LGMD2G, a rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. A total of 300 individuals with ARLGMD were recruited for this study. Among these we identified 8 clinically well characterised LGMD2G cases from 7 unrelated Dravidian families. Clinical examination revealed predominantly proximo - distal form of weakness, scapular winging, muscle atrophy, calf hypertrophy and foot drop, immunoblot showed either complete absence or severe reduction of telethonin. Genetic analysis revealed a novel nonsense homozygous mutation c.32C>A, p.(Ser11*) in three patients of a consanguineous family and an 8 bp homozygous duplication c.26_33dupAGGTGTCG, p.(Arg12fs31*) in another patient. Both mutations possibly lead to truncated protein or nonsense mediated decay. We could not find any functionally significant TCAP mutation in the remaining 6 samples, except for two other polymorphisms, c.453A>C, p.( = ) and c.-178G>T, which were found in cases and controls. This is the first report from India to demonstrate TCAP association with LGMD2G.
Highlights
The seventh form of Autosomal Recessive Limb-Girdle Muscular Dystrophy (LGMD2G; OMIM 601954) is caused by genetic variations in the telethonin gene (NM_003673.3)
For the first time in India, we have performed a comprehensive analysis of LGMD2G, a rare muscle disease caused by telethonin protein deficiency encoded by the TCAP gene
He presented with exertion induced calf muscle pains and progressive toe walking from eight years of age, progressive pectoral girdle, arm and lower limb proximal muscle wasting with weakness, scapular winging and mild foot drop
Summary
The seventh form of Autosomal Recessive Limb-Girdle Muscular Dystrophy (LGMD2G; OMIM 601954) is caused by genetic variations in the telethonin gene ( named as TCAP or titin-cap gene) (NM_003673.3). LGMD2G was first described from Brazil [2]; subsequently it was reported from China [3], Moldavia [4], and Portugal [5]. Onset of this disease is usually in the second decade, with predominant pelvic girdle weakness and associated distal weakness with foot drop [2]. Telethonin plays an important role in the sarcomeric assembly as it joins the two antiparallel titin (Z1-Z2) domains together through beta strand crossing and represents the strongest protein–protein interaction observed so far [9,10,11,12]. TCAP is expected to play a very important role in the sarcomeric assembly
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