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This summary reviews the evidence linking biallelic pathogenic variants in TMEM53 to craniotubular dysplasia, Ikegawa type. The disorder is characterized by skeletal dysplasia manifesting as calvarial and facial bone thickening, vertebral flattening, and notably, visual impairment due to optic canal narrowing. Inheritance is autosomal recessive, and multiple independent families have been reported with this phenotype (PMID:39084544; PMID:39901041).
Genetic evidence is derived from case reports and multi‐patient studies. One study described five affected individuals in four Indian families carrying a homozygous indel variant in TMEM53 (PMID:39084544). In a separate report, two Iranian siblings were shown to harbor a novel homozygous missense variant, specifically c.704G>T (p.Arg235Leu), that co‐segregated with the disease (PMID:39901041). Moreover, a multi‐patient study involving four independent families identified bi‐allelic loss‐of‐function variants, further confirming the mutational spectrum and segregation of TMEM53 variants (PMID:33824347).
Additional genetic findings include a deletion and missense variants across the reported studies. The selection of the c.704G>T (p.Arg235Leu) variant from the Iranian family, which meets the required HGVS guidelines with three‑letter amino acid codes, underscores the consistency in the variant spectrum in TMEM53 associated with this disease.
Functional data have robustly supported the genetic findings. Experimental assessment using Tmem53 knockout mice demonstrated recapitulation of the human skeletal phenotype. Cellular studies revealed that TMEM53 normally localizes to the nuclear envelope of osteoprogenitor cells and functions to dampen BMP-SMAD signaling. Loss of TMEM53 leads to overactive BMP signal transduction, which in turn accelerates osteogenesis and underlies the sclerosing bone dysplasia phenotype observed in patients (PMID:33824347).
The convergence of clinical, genetic, and functional evidence has led to a strong gene-disease association. Multiple probands from unrelated families exhibit co‐segregating variants in TMEM53, and the experimental data clearly elucidate a mechanism whereby loss-of-function leads to dysregulated bone formation. This multi-tiered evidence base validates TMEM53 as a critical gene in the pathogenesis of craniotubular dysplasia, Ikegawa type.
In summary, the integration of segregation data, variant characterization—including the c.704G>T (p.Arg235Leu) change—and compelling functional assays provide a robust framework for diagnostic decision‑making, commercial assay development, and future publication. Clinicians and diagnosticians can confidently include TMEM53 in genetic testing panels for patients showing the characteristic skeletal and visual phenotypes.
Gene–Disease AssociationStrongEvidence from 5 probands in 4 Indian families (PMID:39084544) and 2 probands in an Iranian family (PMID:39901041), along with segregation in 4 families from a multi‐patient study (PMID:33824347), supports a strong gene-disease association. Genetic EvidenceStrongMultiple case reports featuring different classes of variants, including the c.704G>T (p.Arg235Leu) missense change, provide robust genetic evidence with clear co-segregation across independent families. Functional EvidenceStrongKnockout models and cellular assays demonstrate that loss-of-function in TMEM53 results in dysregulated BMP-SMAD signaling, which directly recapitulates the human skeletal phenotype. |