Atypical phenotypes in titinopathies explained by second titin mutations. Issue 2 (24th February 2014)

• Record Type: Journal Article
• Authors: Evilä, Anni; Vihola, Anna; Sarparanta, Jaakko; Raheem, Olayinka; Palmio, Johanna; Sandell, Satu; Eymard, Bruno; Illa, Isabel; Rojas‐Garcia, Ricard; Hankiewicz, Karolina; Negrão, Luis; Löppönen, Tuija; Nokelainen, Pekka; Kärppä, Mikko; Penttilä, Sini; Screen, Mark; Suominen, Tiina; Richard, Isabelle; Hackman, Peter; Udd, Bjarne
• Is Part Of: Annals of neurology. Volume 75:Issue 2(2014:Feb.)
• Page Start: 230
• Page End: 240
• Publication Date: 2014-02-24
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24102
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24102-sec-0001" sec-type="section"> <title>Objective</title> <p>Several patients with previously reported titin gene <italic>(TTN)</italic> mutations causing tibial muscular dystrophy (TMD) have more complex, severe, or unusual phenotypes. This study aimed to clarify the molecular cause of the variant phenotypes in 8 patients of 7 European families.</p> </sec> <sec id="ana24102-sec-0002" sec-type="section"> <title>Methods</title> <p>Clinical, histopathological, and muscle imaging data of patients and family members were reanalyzed. The titin protein was analyzed by Western blotting and <italic>TTN</italic> gene by reverse transcription polymerase chain reaction (RT‐PCR) and Sanger sequencing.</p> </sec> <sec id="ana24102-sec-0003" sec-type="section"> <title>Results</title> <p>Western blotting showed more pronounced C‐terminal titin abnormality than expected for heterozygous probands, suggesting the existence of additional <italic>TTN</italic> mutations. RT‐PCR indicated unequal mRNA expression of the <italic>TTN</italic> alleles in biopsies of 6 patients, 3 with an limb‐girdle muscular dystrophy type 2J (LGMD2J) phenotype. Novel frameshift mutations were identified in 5 patients. A novel A‐band titin mutation, c.92167C>T (p.P30723S), was found in 1 patient, and 1 Portuguese patient with a severe TMD phenotype proved to be homozygous for the previously reported Iberian TMD mutation.</p> </sec> <sec id="ana24102-sec-0004" sec-type="section"> <title>Interpretation</title> <p>The unequal expression levels of <italic>TTN</italic> transcripts in 5 probands suggested severely reduced expression of the frameshift mutated allele, probably through nonsense‐mediated decay, explaining the more severe phenotypes. The Iberian TMD mutation may cause a more severe TMD rather than LGMD2J when homozygous. The Finnish patient compound heterozygous for the FINmaj TMD mutation and the novel A‐band titin missense mutation showed a phenotype completely different from previously described titinopathies. Our results further expand the complexity of muscular dystrophies caused by <italic>TTN</italic> mutations and suggest that the coexistence of second mutations may constitute a more common general mechanism explaining phenotype variability. Ann Neurol 2014;75:230–240</p> </sec> </abstract>