Monday, April 15, 2024

MACF1 mutations and spectraplakinopathy

Inspired by a patient

Kang L, Liu Y, Jin Y, Li M, Song J, Zhang Y, Zhang Y, Yang Y. Mutations of MACF1, Encoding Microtubule-Actin Crosslinking-Factor 1, Cause Spectraplakinopathy. Front Neurol. 2020 Jan 15;10:1335. doi: 10.3389/fneur.2019.01335. PMID: 32010038; PMCID: PMC6974614.


As a member of spectraplakin family of cytoskeletal crosslinking proteins, microtubule-actin crosslinking factor 1 (MACF1) controls cytoskeleton network dynamics. Knockout of Macf1 in mice resulted in the developmental retardation and embryonic lethality. Spectraplakinopathy type I, a novel neuromuscular condition characterized by periodic hypotonia, lax muscles, joint contracture, and diminished motor skill, was reported to be associated with heterozygous genomic duplication involving the MACF1 loci, with incomplete penetrance and highly variable clinical presentation in a single pedigree. In this study, parental-derived compound heterozygous novel missense mutations of MACF1, c.1517C>T (p.Thr506Ile) and c.11654T>C (p.Ile3885Thr), were found to co-segregate with disease status in two affected brothers presenting with progressive spastic tetraplegia, dystonia, joint contracture, feeding difficulty and developmental delay. We speculated that MACF1 mutations cause spectraplakinopathy inherited in an autosomal recessive manner. Our clinical findings expanded the phenotype of this neuromuscular disorder and provided new insights into the function of MACF1.

Dobyns WB, Aldinger KA, Ishak GE, Mirzaa GM, Timms AE, Grout ME, Dremmen MHG, Schot R, Vandervore L, van Slegtenhorst MA, Wilke M, Kasteleijn E, Lee AS, Barry BJ, Chao KR, Szczałuba K, Kobori J, Hanson-Kahn A, Bernstein JA, Carr L, D'Arco F, Miyana K, Okazaki T, Saito Y, Sasaki M, Das S, Wheeler MM, Bamshad MJ, Nickerson DA; University of Washington Center for Mendelian Genomics; Center for Mendelian Genomics at the Broad Institute of MIT and Harvard; Engle EC, Verheijen FW, Doherty D, Mancini GMS. MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. Am J Hum Genet. 2018 Dec 6;103(6):1009-1021. doi: 10.1016/j.ajhg.2018.10.019. Epub 2018 Nov 21. PMID: 30471716; PMCID: PMC6288423.


To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.

Moffat JJ, Ka M, Jung EM, Smith AL, Kim WY. The role of MACF1 in nervous system development and maintenance. Semin Cell Dev Biol. 2017 Sep;69:9-17. doi: 10.1016/j.semcdb.2017.05.020. Epub 2017 Jun 1. PMID: 28579452; PMCID: PMC5583038.


Microtubule-actin crosslinking factor 1 (MACF1), also known as actin crosslinking factor 7 (ACF7), is essential for proper modulation of actin and microtubule cytoskeletal networks. Most MACF1 isoforms are expressed broadly in the body, but some are exclusively found in the nervous system. Consequentially, MACF1 is integrally involved in multiple neural processes during development and in adulthood, including neurite outgrowth and neuronal migration. Furthermore, MACF1 participates in several signaling pathways, including the Wnt/β-catenin and GSK-3 signaling pathways, which regulate key cellular processes, such as proliferation and cell migration. Genetic mutation or dysregulation of the MACF1 gene has been associated with neurodevelopmental and neurodegenerative diseases, specifically schizophrenia and Parkinson's disease. MACF1 may also play a part in neuromuscular disorders and have a neuroprotective role in the optic nerve. In this review, the authors seek to synthesize recent findings relating to the roles of MACF1 within the nervous system and explore potential novel functions of MACF1 not yet examined.

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