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Defect in Muscle Cell Fusion Gene Linked to Rare Autosomal Recessive Syndrome

NEW YORK (GenomeWeb) – A new exome sequencing study suggests that a rare inherited muscle disorder called Carey-Fineman-Ziter syndrome (CFZS) stems from mutations that alter a plasma membrane protein involved in skeletal muscle cell, or myoblast, fusion into muscle fibers.

Researchers from Boston Children's Hospital, Harvard Medical School, the National Human Genome Research Institute (NHGRI), and elsewhere used exome and targeted sequencing to search for suspicious mutations in three families affected by CFZS, a condition associated with facial weakness, spinal curvature, a cleft palate, and a chin that is unusually small or retracted. Their search led to autosomal recessive mutations in the myomaker protein-coding gene MYMK. The findings appeared online today in Nature Communications.

"This discovery will improve physicians' ability to diagnose this disease and offer families accurate genetic counselling and treatment," first author Irini Manoli, a medical genomics and metabolic genetics researcher at NHGRI, said in a statement. She noted that the rare genetic syndrome "provides novel insights into the effects of muscle development on craniofacial and skeletal bone formation."

The facial symptoms of CFZS sometimes resemble those described in another rare condition called Moebius syndrome, Manoli and her co-authors explained, which sometimes leads to CFZS misdiagnoses. In an effort to eventually improve disease detection and treatment, the team — which included members of the Moebius Syndrome Research Consortium — set out to find not only Moebius syndrome contributors, but also the genetic culprits behind CFZS.

Through detailed phenotyping and clinical testing on dozens of individuals with Moebius syndrome or similar conditions, the researchers narrowed in on three families from the US or New Zealand, each with two CFZS-affected children. Exome sequencing experiments by collaborators at different centers using Illumina HiSeq 2000 or 2500 instruments led to the suspicious MYMK mutations.

Through targeted MYMK gene sequencing in more than 300 other individuals with facial paralysis and other symptoms, the team tracked down additional CFZS cases, bringing the tally up to eight affected individuals from five families. In the affected individuals, the recessive MYMK mutations typically included two alleles with reduced gene function, the investigators noted, or one of these hypomorphic alleles coupled with a null MYMK allele.

The researchers' subsequent cell line, zebrafish, and gene editing experiments suggested that MYMK alterations can produce muscle problems consistent with those found in CFZS, since dialing down levels of the gene led to defective muscle development and unusual skeletal features — changes that could be avoided in the zebrafish model by adding back a normal version of the MYMK gene.

"[T]he ability to genetically rescue the mutant phenotype in zebrafish lends hope for future therapies that restore MYMK function in muscle and lessen any progressive features of this disorder," the authors concluded.