This report describes myofibrillar myopathy 4, which shows autosomal dominant inheritance. The human gene implicated in this disease is LDB3, sometimes referred to as ZASP, an actin-binding protein commonly found in muscle. There is a high-ranking ortholog of LDB3 in Drosophila, Zasp52. Several alleles have been generated of Zasp52, including alleles carrying RNAi targeting constructs, generated by insertional mutagenesis, and classical hypomorphic alleles.
LDB3 is also associated with dilated cardiomyopathy-1C with or without left ventricular noncompaction (CMD1C), left ventricular noncompaction-3 (LVNC3), and familial hypertrophic cardiomyopathy-24 (MIM:601493).
The human gene LDB3 has not been introduced into flies.
Overexpression of Zasp52 in fly indirect flight muscles caused it to form protein aggregates, and Z-discs were larger than in controls. The aggregation phenotype was absent when Zasp52 mutant alleles lacking either the LIM domains or ZM domain were overexpressed, indicating that they are required for the pathogenic phenotype.
[updated Feb. 2020 by FlyBase; FBrf0222196]
Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%. A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. Peripheral neuropathy is present in about 20% of affected individuals. Overt cardiomyopathy is present in 15%-30%. [from Gene Reviews, Myofibrillar Myopathy; 2017.08.14]
Myofibrillar myopathy (MFM) is a noncommittal term that refers to a group of morphologically homogeneous, but genetically heterogeneous chronic neuromuscular disorders. [from MIM:601419; 2017.08.14]
[MYOPATHY, MYOFIBRILLAR, 4; MFM4](https://omim.org/entry/609452)
[LIM DOMAIN-BINDING 3; LDB3](https://omim.org/entry/605906)
First clinical symptoms usually occur in the sixth decade, the disease progression is very slow and patients remain ambulatory until very late age. Patients present with muscle weakness, similar to myotilinopathy. Peripheral neuropathy and cardiac involvement are associated features in a minority of cases. (Adapted from Olivé et al. 2014 pubmed:23995273.)
Selcen and Engel 2005 (pubmed:15668942) reported 11 unrelated patients with MFM4. Age at onset ranged from 44 to 73 years (mean, 54 years). All patients presented with muscle weakness except 1 who presented with palpitations and mildly increased serum creatine kinase. All patients showed MFM on skeletal muscle biopsy, including pleomorphic hyaline, granular, and amorphous deposits on trichrome staining. Ten patients had intensely congophilic hyaline structures, indicating amyloid material. [from MIM:609452, 2020.02.06]
Myofibrillar myopathy-4 (MFM4) is caused by heterozygous mutation in the ZASP gene (LDB3; MIM:605906) on chromosome 10. [from MIM:609452, 2020.02.06]
Myofibrillar myopathies (MFMs) are hereditary muscle diseases characterized by distinct histopathological features of protein aggregation pathology. The most prominent findings are a focal disintegration of myofibrils predominantly at the Z-disc level and sarcoplasmic protein aggregates that show an accumulation of several proteins. (From Kley et al. 2016, pubmed:27389816.)
A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM4 is characterized by distal and proximal muscle weakness with signs of cardiomyopathy and neuropathy. (From UniProt:O75112, 2020.02.06.)
One to one: 1 human gene to 1 Drosophila gene.
Single, high-ranking ortholog of human LDB3.
