Novel TCAP Mutation c.32C>A Causing Limb Girdle Muscular Dystrophy 2G

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.

A new case of limb girdle muscular dystrophy 2G in a Greek patient, founder effect and review of the literature

“…On the contrary, distal involvement is frequently described in LGMD2G patients, sometimes also at early stages [6-14-19], especially in lower limbs, presenting with foot-drop and involvement of tibialis anterior muscles. As well as in our patient, this feature was predominant also in other subjects with LGMD2G [6][7][8][9][10][11][12][13][14][15][16][17]. Respiratory involvement or cardiomyopathy was not reported in both cases, consistently with the majority of previous reports; extrasystolia had been described only in the Turkish patient.…”

Clinical, pathological, imaging, and genetic characterization in a Taiwanese cohort with limb-girdle muscular dystrophy

“…In our cohort, all four patients with LGMD2G carried the same homozygous hot spot mutation, c.26_33dup (p.Glu12Argfs*20), which has previously been reported only in three Chinese patients and one Indian patient [30,31]. Taken together, our results further emphasize the potential founder effect of this mutation in East and South Asia.…”

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

“…A cohort study of 300 patients with autosomal recessive LGMD identified eight patients with LGMD 2G, who either had no or reduced telethonin protein levels [ 160 ]. Clinical features were predominantly progressive proximo-distal muscle weakness, scapular winging and calf hypertrophy.…”

“…A number of studies indicate a causative role of homozygous TCAP variants resulting in premature stop codons in LGMD 2G. Analyses of skeletal muscle biopsies suggest lack of functional telethonin protein [ 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 ]. However, findings depend on the epitopes of the antibodies used, so it is currently not clear how much nonsense mediate decay contributes to the disease mechanism.…”