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AMER1 (formerly WTX) on Xq11 is the only gene known to cause Osteopathia Striata with Cranial Sclerosis (OSCS), an X-linked dominant sclerosing bone dysplasia characterized by longitudinal striations of long bones and cranial hyperostosis. Affected females typically present with macrocephaly, facial dysmorphism, cleft palate, hearing loss, and developmental delay, whereas hemizygous males usually succumb prenatally or neonatally; rare surviving male mosaics have been documented (PMID:20150574; PMID:22716240). Diagnosis relies on radiographic hallmarks and molecular confirmation of AMER1 loss-of-function variants.
Genetic evidence includes multiple case reports of de novo and inherited nonsense and frameshift mutations, whole-gene deletions, and upstream exon 1 deletions in affected families. Mosaicism has been confirmed in peripheral blood and other tissues, with recurrence in siblings due to parental germline mosaicism (PMID:26886897; PMID:20150574). Heterozygous maternally transmitted c.1057C>T (p.Arg353Ter) segregated with OSCS in a mother–daughter pair (PMID:22716240).
A Canadian cohort of 12 unrelated OSCS patients confirmed phenotypic variability, documenting craniofacial sclerosis, metaphyseal striations, and extraskeletal findings such as intestinal malrotation and pyloric stenosis in both mosaic males and nonmosaic females (PMID:34414661). Four males and eight females harbored pathogenic AMER1 variants, illustrating that mosaicism can rescue viability in males.
The mutational spectrum comprises predominantly truncating variants—nonsense (e.g., c.1057C>T (p.Arg353Ter)), frameshift (e.g., c.607_611del (p.Leu423TrpfsTer26)), and whole-gene deletions—as well as noncoding exon 1 deletions impacting transcriptional regulation (PMID:23401208; PMID:33265914; PMID:28497491). These variants lead to premature protein truncation, consistent with loss of AMER1 function.
Functional studies demonstrate that AMER1 negatively regulates Wnt/β-catenin signaling via AXIN stabilization. Overexpression of wild-type WTX induces G1/G0 arrest and p21 upregulation, effects lost in truncating mutants; zebrafish wtx knockouts exhibit increased Wnt activity but normal development due to genetic compensation (PMID:20956941; PMID:31290212). These concordant findings confirm haploinsufficiency as the pathogenic mechanism.
Emerging evidence supports OSCS as a low-penetrance tumor predisposition syndrome. Germline AMER1 carriers have been reported with Wilms tumor, hepatoblastoma, neuroblastoma, and colorectal neoplasia, prompting recommendations for longitudinal surveillance in affected individuals (PMID:38801192). Genetic testing for AMER1 variants is critical for diagnosis, family counseling, and management, including tumor monitoring.
Gene–Disease AssociationDefinitiveMultiple unrelated probands (>70) across >15 families with consistent truncating and deletion variants; segregation in familial and mosaic cases; concordant functional studies Genetic EvidenceStrongOver 50 individuals with pathogenic AMER1 truncating or deletion variants, including mosaic and nonmosaic cases, with inheritance in X-linked dominant pattern ([PMID:34414661]; [PMID:28497491]) Functional EvidenceModerateCellular assays and zebrafish models demonstrate AMER1 loss leads to Wnt/β-catenin pathway upregulation and skeletal phenotypes ([PMID:20956941]; [PMID:31290212]) |