Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
MARS encodes the cytosolic methionyl-tRNA synthetase that catalyzes the ligation of methionine to its cognate tRNA, a critical step in protein biosynthesis. Biallelic MARS variants underlie interstitial lung and liver disease (ILLD), a severe early-onset pulmonary alveolar proteinosis syndrome now classified as MONDO:0014206. Affected infants present in the first months of life with diffuse interstitial pulmonary pathology, hypoxemic respiratory failure, postnatal growth retardation, global developmental delay and systemic features including anemia. This autosomal recessive condition is genetically and mechanistically distinct from dominantly inherited Charcot-Marie-Tooth disease type 2U caused by heterozygous MARS mutations. Early recognition of the MARS-deficient PAP phenotype enables timely genetic counseling and potential metabolic therapy. Recent reports have expanded the allelic spectrum and demonstrated functional rescue with methionine supplementation.
Genetic analyses in Family 1 identified two male siblings with compound heterozygous missense variants c.433G>A (p.Asp145Asn) and c.2404T>C (p.Phe802Ser) (PMID:28148924). A second unrelated infant carried a truncating variant c.2158C>T (p.Gln720Ter) and a tri-nucleotide insertion c.893_894insTCG (p.Arg299dup) (PMID:30271085). All variants segregated in trans with disease under an autosomal recessive model. Overall, three probands have been described across two unrelated families, supporting a strong genetic association. The variant spectrum includes missense (n=2), truncating (n=1) and insertion alleles (n=1) clustered in the catalytic domain. No homozygous loss-of-function alleles are present in population databases, and no recurrent or founder variants have been documented.
Segregation analysis confirmed that each parent is a heterozygous carrier with no additional affected relatives identified (PMID:28148924, PMID:30271085). This yields zero informative meioses beyond the two sibships under study. Although parental carrier status supports trans configuration, extended pedigree data are lacking. Lack of consanguinity and absence of additional kin affected highlight the rarity of reported cases. These data provide limited segregation evidence but align with autosomal recessive inheritance. Future family studies will be required to strengthen segregation support.
In vitro aminoacylation assays of mutant MARS proteins demonstrate residual activity reduced to 18 ± 6% for p.Phe370Leu and 16 ± 6% for p.Ile523Thr, confirming a hypomorphic loss-of-function mechanism (PMID:24103465). Homology modeling localizes these variants to the methionine binding pocket, supporting structural disruption. Thermal stability and kinetic analyses of PAP-associated mutants (e.g., p.Ser567Leu) reveal impaired methionine recognition and reduced tRNA charging at physiological temperatures (PMID:29775242). Yeast complementation assays further validate variant pathogenicity. Patient-derived fibroblast studies show decreased aminoacylation activity, and methionine supplementation restores enzymatic function in vitro (PMID:32833345). Together, these findings confirm that biallelic loss-of-function in MARS underlies the ILLD phenotype.
Clinically, ILLD patients present with diffuse interstitial pulmonary pathology, hypoxemic respiratory failure, postnatal growth retardation, global developmental delay, hepatopathy and anemia (PMID:28148924, PMID:30271085). Additional features such as thrombocytosis, nephrolithiasis and acetabular dysplasia have been reported, expanding the phenotypic spectrum. Whole lung lavage is the mainstay for pulmonary alveolar proteinosis management in affected siblings. Remarkably, methionine supplementation and a high-protein diet led to sustained respiratory improvement in homozygous p.Arg598Cys patients (PMID:32833345). This suggests that targeted metabolic adjunctive therapy may modify disease course. Systematic trials are warranted to evaluate long-term benefits of such interventions.
A potential confounder is the monoallelic p.Arg618Cys MARS variant, which causes dominant Charcot-Marie-Tooth disease type 2U in some families and also appears in ILLD when in compound heterozygosity (PMID:29655802). Yeast complementation suggests p.Arg618Cys retains partial function, indicating dominant-negative or gain-of-function effects in neuropathy. This underscores allelic heterogeneity and variable mechanisms across tissues. However, the recessive ILLD phenotype is consistently associated with biallelic loss-of-function variants. No studies refute the MARS–ILLD association, though modifier factors may influence phenotypic variability. Future work should delineate how specific alleles modulate clinical outcomes.
Overall, the association between HGNC:6898 (MARS) and MONDO:0014206 (ILLD) is supported by multiple unrelated probands with biallelic pathogenic variants and concordant functional data demonstrating loss of methionyl-tRNA synthetase activity. Genetic and functional evidence meets ClinGen criteria for a Strong gene-disease association. Identification of MARS variants has immediate diagnostic utility and informs prognosis, genetic counseling, and therapeutic options including targeted metabolic support. Prospective natural history studies and treatment trials will refine management strategies. Whole-exome sequencing or targeted gene panels should be considered in infants with unexplained interstitial lung disease and multisystem involvement. Key take-home: Biallelic MARS loss-of-function underlies a severe early-onset pulmonary proteinosis syndrome responsive to metabolic intervention.
Gene–Disease AssociationStrong3 probands across two unrelated families; functional studies demonstrate loss-of-function concordant with disease Genetic EvidenceModerate3 unrelated probands with compound heterozygous MARS variants, including missense and truncating changes, consistent with autosomal recessive inheritance Functional EvidenceModerateIn vitro aminoacylation assays show 16–18% residual activity [PMID:24103465]; thermal stability and catalytic defects confirmed [PMID:29775242]; rescue by methionine supplementation in patient fibroblasts [PMID:32833345] |