title: Use of SNP array analysis to identify a novel TRIM32 mutation in limb-girdle muscular dystrophy type 2H.
abstract: Molecular diagnosis of monogenic diseases with high genetic heterogeneity is usually challenging. In the case of limb-girdle muscular dystrophy, multiplex Western blot analysis is a very useful initial step, but that often fails to identify the primarily affected protein. We report how homozygosity analysis using a genome-wide SNP array allowed us to solve the diagnostic enigma in a patient with a moderate form of LGMD, born from consanguineous parents. The genome-wide scan performed on the patient's DNA revealed several regions of homozygosity, that were compared to the location of known LGMD genes. One such region indeed contained the TRIM32 gene. This gene was previously found mutated in families with limb-girdle muscular dystrophy type 2H (LGMD2H), a mild autosomal recessive myopathy described in Hutterite populations and in 4 patients with a diagnosis of sarcotubular myopathy. A single missense mutation was found in all these patients, located in a conserved domain of the C-terminal part of the protein. Another missense mutation affecting the N-terminal part of TRIM32, observed in a single consanguineous Bedouin family, was reported to cause the phenotypically unrelated and genetically heterogeneous Bardet-Biedl syndrome, defining the BBS11 locus. Sequencing of TRIM32 in our patient revealed a distal frameshift mutation, c.1753_1766dup14 (p.Ile590Leu fsX38). Together with two recently reported mutations, this novel mutation confirms that integrity of the C-terminal domain of TRIM32 is necessary for muscle maintenance.
authors.affiliation: Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. mireille.cossee@cch.aphp.fr
authors.forename: Mireille
authors.initials: M
authors.lastname: Cossée
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.forename: Claire
authors.initials: C
authors.lastname: Seguela
authors.forename: Michel
authors.initials: M
authors.lastname: Mohr
authors.forename: France
authors.initials: F
authors.lastname: Leturcq
authors.forename: Hulya
authors.initials: H
authors.lastname: Gundesli
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
mesh_terms: D018912:Arabs / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005602:France; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D005819:Genetic Markers; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C094027:TRIM32 protein, human; D044767:Ubiquitin-Protein Ligases