Objective: To identify the gene and specific mutation underlying hyaline body myopathy in the family studied.
Methods: A microsatellite-based whole genome scan was performed. Linkage analysis assumed autosomal dominant inheritance and equal allele frequencies. A candidate gene approach within the linked interval and direct sequencing were used for mutation detection.
Results: Initial analysis indicated a maximum lod score of 3.01 at D14S1280. High-density mapping surrounding the linked locus was performed. Multipoint analysis showed that the linked region with a maximum lod score of 3.01 extended from D14S742 to D14S608 with a peak non-parametric linkage (NPL) score of 3.75 at D14S608. The myosin heavy chain genes MYH6 and MYH7 map to the region between D14S742 and D14S1280. Sequence analysis of the coding regions of MYH7 revealed an A→T transversion at nucleotide position 25596 (M57965) resulting in a histidine-to-leucine amino acid change at residue 1904 (H1904L).
Conclusion: Pathogenicity of the MYH7 H1904L mutation most likely results from disruption of myosin heavy chain assembly or stability of the sarcomeric protein. The MYH7 tail domain mutation results in an inclusion body myopathy with an apparent absence of hypertrophic cardiomyopathy usually associated with mutations of this gene.