Genetic heterogeneity in 30 German patients with oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is due to short elongations of a polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1) gene. Originally GCG expansions in which (GCG)6 is extended to (GCG)7–13 were found. Subsequently five further genotypes with additional GCA– and GCG–trinucleotides were identified in single OPMD patients. This indicated larger genetic heterogeneity and showed that unequal crossing–over and not replication slippage must be the underlying mechanism of elongation.We performed sequencing of the PABPN1 gene in 30 German OPDM index patients to determine the exact genotype. The original GCG expansion ranging from (GCG)8 to (GCG)11 was found in 22 patients. In 8 patients, however, three different elongated alleles other than classical (GCG)7–13 were observed. Two of these genotypes had already been identified in Japanese patients. One genotype was recently identified showing (GCG)6 followed by inserted (GCA)3GCG in four unrelated patients. This study further supports the theory of unequal crossing over as the molecular mechanism leading to elongation. It shows that other genotypes than classical (GCG)7–13 are rather common in German OPMD patients. The data imply that there is no single founder effect in German OPMD patients.

[1]  S. Zierz,et al.  GCG Repeats and phenotype in oculopharyngeal muscular dystrophy , 2001, Muscle & nerve.

[2]  D. Robinson,et al.  Oculopharyngeal muscular dystrophy (OPMD): analysis of the PABPN1 gene expansion sequence in 86 patients reveals 13 different expansion types and further evidence for unequal recombination as the mutational mechanism , 2005, Human Genetics.

[3]  B. Brais.  Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease , 2003, Cytogenetic and Genome Research.

[4]  T. Hanafusa,et al.  [Preferential distal muscle involvement in case of oculopharyngeal muscular dystrophy with (GCG) 13 expansion]. , 2003, Rinsho shinkeigaku = Clinical neurology.

[5]  W. Kress,et al.  Unusual triplet expansion associated with neurogenic changes in a family with oculopharyngeal muscular dystrophy , 2001, Neuropathology : official journal of the Japanese Society of Neuropathology.

[6]  S. Ehrlich,et al.  Replication slippage involves DNA polymerase pausing and dissociation , 2001, The EMBO journal.

[7]  E. Hoffman,et al.  Unique PABP2 mutations in "Cajuns" suggest multiple founders of oculopharyngeal muscular dystrophy in populations with French ancestry. , 1999, American journal of medical genetics.

[8]  Mika Nakamoto,et al.  Unequal crossing-over in unique PABP2 mutations in Japanese patients: a possible cause of oculopharyngeal muscular dystrophy. , 2002, Archives of neurology.

[9]  L. Hoefsloot,et al.  Oculopharyngeal muscular dystrophy (OPMD) due to a small duplication in the PABPN1 gene , 2003, Human mutation.

[10]  B. Brais,et al.  Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy , 1998, Nature Genetics.

[11]  S. Blumen,et al.  Homozygotes for oculopharyngeal muscular dystrophy have a severe form of the disease , 1999, Annals of neurology.

[12]  B. Brais,et al.  (GCG)11 founder mutation in the PABPN1 gene of OPMD Uruguayan families , 2005, Neuromuscular Disorders.

[13]  S. Blumen,et al.  Oculopharyngeal MD among Bukhara Jews is due to a founder (GCG)9 mutation in the PABP2 gene , 2000, Neurology.

[14]  S. Di Giovanni,et al.  GCG genetic expansions in Italian patients with oculopharyngeal muscular dystrophy , 2000, Neurology.

[15]  J. Weissenbach,et al.  The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac alpha and beta myosin heavy chain genes on chromosome 14q11.2-q13. , 1995, Human molecular genetics.

[16]  M. Kase,et al.  Oculopharyngeal muscular dystrophy in a Japanese family with a short GCG expansion (GCG)11 in PABP2 gene , 2000, Neuromuscular Disorders.

[17]  J. Weissenbach,et al.  The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac α and β myosin heavy chain genes on chromosome 14q11.2−q13 , 1995 .