---

Associate Professor Kathryn North
Sydney
Australia

---

Authors
Mills M. Yang N. Weinberger R. Vander Woude DL. Beggs AH. Easteal S. North K.
Institution: Neurogenetics Research Unit, Children's Hospital at Westmead, Westmead, Sydney, NSW 2145, Australia.

Title: Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy.

Source: Human Molecular Genetics. 10(13):1335-46, 2001 Jun 15.

Abstract
The alpha-actinins are a multigene family of four actin-binding proteins related to dystrophin. The two skeletal muscle isoforms of alpha-actinin (ACTN2 and ACTN3) are major structural components of the Z-line involved in anchoring the actin-containing thin filaments. In humans, ACTN2 is expressed in all muscle fibres, while ACTN3 expression is restricted to a subset of type 2 fibres. We have recently demonstrated that alpha-actinin-3 is absent in approximately 18% of individuals in a range of human populations, and that homozygosity for a premature stop codon (577X) accounts for most cases of true alpha-actinin-3 deficiency. Absence of alpha-actinin-3 is not associated with an obvious disease phenotype, raising the possibility that ACTN3 is functionally redundant in humans, and that alpha-actinin-2 is able to compensate for alpha-actinin-3 deficiency. We now present data concerning the expression of ACTN3 in other species. Genotyping of non-human primates indicates that the 577X null mutation has likely arisen in humans. The mouse genome contains four orthologues which all map to evolutionarily conserved syntenic regions for the four human genes. Murine Actn2 and Actn3 are differentially expressed, spatially and temporally, during embryonic development and, in contrast to humans, alpha-actinin-2 expression does not completely overlap alpha-actinin-3 in postnatal skeletal muscle, suggesting independent function. Furthermore, sequence comparison of human, mouse and chicken alpha-actinin genes demonstrates that ACTN3 has been conserved over a long period of evolutionary time, implying a constraint on evolutionary rate imposed by continued function of the gene. These observations provide a real framework in which to test theoretical models of genetic redundancy as they apply to human populations. In addition we highlight the need for caution in making conclusions about gene function from the phenotypic consequences of loss-of-function mutations in animal knockout models.

---

Authors
Tan P. Briner J. Boltshauser E. Davis MR. Wilton SD. North K. Wallgren-Pettersson C. Laing NG.
Institution: Australian Neuromuscular Research Institute, QEII Medical Centre, Nedlands, Western Australia.

Title: Homozygosity for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in a patient with severe infantile nemaline myopathy.

Source: Neuromuscular Disorders. 9(8):573-9, 1999 Dec.

Abstract
The nemaline myopathies are muscle disorders of variable severity and age of onset, with characteristic nemaline bodies in the sarcoplasm. Genes for dominant (NEM1) and recessive (NEM2A) nemaline myopathy have been localised to chromosomes one and two, respectively. A missense mutation in the alpha-tropomyosin gene (TPM3) has been associated with NEM1 in one family. Probands from 76 other nemaline myopathy families have now been screened for TPM3 mutations. One proband, who was not noted to have any weakness neonatally, but who died at 21 months of age, was shown to be homozygous for a single strand conformation polymorphism (SSCP) in skeletal-muscle-specific exon 1 of TPM3. Sequencing revealed homozygosity for a nonsense mutation at codon 31 (CAG to TAG). The patient should have no functioning alpha-tropomyosin slow protein. The nemaline bodies in this patient were exclusively in type one fibres, consistent with the expression of TPM3 only in type one fibres.

---

Nemaline Myopathy Caused by Mutations in the Muscle Skeletal-Actin(ACTA1) Gene
Nemaline Myopathy (NM) is a muscle disease that varies in clinical severity. Our scientists, with a multi-national team, recently identified mutations in the alpha actin gene responsible for one form of this disease. Our subsequent study describes our clinical and laboratory observations.

---

Nemaline Myopathy: A Clinical Study of 143 Cases
Clinical Study - Nemaline Myopathy: Our researchers described the largest series nemaline myopathy cases and have enabled doctors to distinguish clinical features. This will provide families with accurate information regarding this disorder in their children.

---

This page was last updated: March 23, 2008
Copyright: David McDougall. 1999-2008
Contact: davidmcd_@hotmail.com