The complexity of simple disorders

Abstract

Two recent publications highlight a growing realization that even so-called simple genetic disorders, i.e. those caused by Mendelian segregation of mutations at a single locus, are more complex than was initially thought. Weiler et al.1 Weiler T. et al. Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier genes. Hum. Mol. Genet. 1999; 8: 871-877 Crossref PubMed Scopus (161) Google Scholar studied two muscle disorders: limb girdle muscular dystrophy 2B (LGMD2B), which is characterized by weakness and wasting of the muscles of the pelvic and shoulder girdles; and the milder disorder Miyoshi myopathy (MM), which affects more distal muscles. Before this work, it was suspected that the same gene was involved in LGMD2B and MM; linkage analysis had implicated human chromosome 2p13 in both cases and two families affected by both disorders had been described. Weiler et al. showed that LGMD2B and MM patients from one of these families had the same mutation in a recently cloned gene, dysferlin (DYSF). They also developed an antibody to the DYSF protein and compared protein expression in the LGMD2B and MM patients. The same pattern and level of expression was observed, indicating that the protein is affected to the same degree in the two disorders. This implies that additional factors (genetic and/or environmental) must modify the expression of the mutation.