NOVEL FHL1 MUTATIONS IN FATAL AND BENIGN REDUCING BODY MYOPATHY

Abstract

Reducing body myopathy (RBM) is a rare disorder characterized pathologically by the presence of intracytoplasmic inclusions strongly stained by menadione-NBT (nitroblue tetrazolium) staining in the absence of the substrate α-glycerophosphate. The causative gene for RBM was recently identified as FHL1 on chromosome Xq27 encoding four and a half LIM domains 1.1 FHL1 is a 32 kDa protein, composed of four LIM domains preceded by a single N-terminal zinc finger. FHL1 is highly expressed in skeletal muscle and heart. Here, we searched for FHL1 mutations in three sporadic cases2-4 and one familial case5 of RBM we previously reported. ### Methods. All clinical materials used in this study were obtained for diagnostic purpose with informed consent. Patient 1 and patient 2 have fatal infantile form,2,3 and patient 3 has adult-onset form.4 Patients 4 (son) and 5 (his mother) had familial cases.5 We directly sequenced all exons and their flanking intronic regions of FHL1 in the five RBM patients and 250 Japanese controls. Frozen muscle specimens were examined by immunohistochemistry and immunoblotting using standard technique. ### Results. We identified four novel mutations in FHL1 : a heterozygous missense mutation of c.449G>A (p.C150Y) in patient 1 and c.302G>T (p.C101F) in patient 2, an in-frame 9 bp deletion at c.304-312delAAGGGGTGC (p.102-104delKFC) in patient 3, and a hemizygous mutation c.310T>C (p.C104R) in patient 4. The mother (patient 5) had the same mutation in heterozygous mode. All mutations we identified are located in the second LIM domain of FHL1 (figure e-1 on the Neurology ® Web site at www.neurology.org). Immunohistochemical analysis of …