The first Italian family with tibial muscular dystrophy caused by a novel titin mutation

Abstract

Tibial muscular dystrophy (TMD) or Udd myopathy is an autosomal dominant distal myopathy with late onset, at first described in the Finnish population. We report here the first Italian cases of TTN mutated titinopathy. The proband, a 60 year-old female, had the first muscular signs at the age of 59 years, with difficulty in walking and right foot drop. Muscle imaging showed selective fatty degenerative change in the anterior compartment of leg muscles. Her 67 year-old brother, started to show muscle weakness, pain at lower limbs and hypertrophy of calf muscles at the age of 66 years. Their mother began to show foot drop and impaired walking from the age of 60 years. Other relatives are reported to be affected in a similar way. Because the phenotype appeared compatible with TMD, we analyzed the TTN gene in the DNA of the proband and we identified a heterozygous mutation 293326A>C. This mutation is also present in the brother and in the other affected individuals of the same family. The mutation predicts a His33378Pro change located next to the previously known Belgian TMD mutation. The mutation was not found in 100 Italian control DNA samples. Then, since the introduction of a proline in the last domain of titin was previously known to cause TMD in French families, we can conclude that this missense mutation is the obvious pathogenetic mutation in the affected patients. No other disease causing mutations in the TTN gene have so far been reported in the Italian population.

Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure

“…Titin is a large protein (4.20 MDa) that extends from the Z-disk to the M-line within the sarcomere, and it is composed of four major domains: Z-disc, I-band, A-band and M-line ( Figure 5). All four HMERF mutations detected by other groups and our study were consistently located in the A-band domain, while mutations in tibial muscular dystrophy (TMD) (MIM #600334), [19][20][21][22][23][24] limb-girdle muscular dystrophy type 2J (LGMD2J) (#608807) 19,25 and early-onset myopathy with fatal cardiomyopathy (#611705) 26 were located in the M-line domain. HMERF and TMD have some common clinical characteristics, such as autosomal dominant inheritance with onset in adulthood and strong involvement of the tibialis anterior muscle.…”

Structural insight into M-band assembly and mechanics from the titin-obscurin-like-1 complex

“…An 11-bp deletion/insertion at position 293,269-293,279 of the titin gene (FINmaj) leads to the exchange of four sequential amino acids in M10 in Finnish patients (17), resulting in the M10 35EVTW38 to VKEK variation; a point mutation at position 293,357 leads to the exchange of M10 Leu64 to Pro in French patients (17), and a point mutation at position 293,329 leads to the exchange of I55 to N in Belgian patients. Very recently, the variation M10 H54 to P has been found in Italian patients (9). The structure of the M10-OL1 complex reveals that these disease-linked residues are not directly involved in the proteinprotein interface (Fig.…”

“…Tibial muscular dystrophy (TMD) and limb girdle muscular dystrophy 2J (LGMD2J) are caused by several missense or deletion/ substitution mutations in titin M10 (9,10), while larger deletions of the titin C terminus cause Salih myopathy (11). Most of these mutations weaken or abrogate binding of obscurin/obsl1 to the M-band (6) and cause gradual failure of sarcomere maintenance.…”

Neuromuscular disorders and 2010: recent advances

“…Pollazzon and co-workers [6] described a new heterozygous TTN mutation in an Italian family. Clinical features of the family were mainly characterized by loss of ankle dorsiflexion, hypotrophy of the anterior compartment of the lower leg, with onset from the 5th decade.…”