TMEM231 – Meckel Syndrome

Meckel syndrome (MKS) is a rare, lethal autosomal recessive ciliopathy characterized by occipital encephalocele, polycystic kidneys, postaxial polydactyly, liver fibrosis and central nervous system malformations. The primary cilium is disrupted, leading to multisystem dysfunction. Biallelic variants in TMEM231 impair ciliary structure and function in affected fetuses.

Genetic evidence for TMEM231 emerged in 2013 when exome sequencing in two consanguineous families identified homozygous splice (c.439-1G>C) and missense (c.664G>T (p.Val222Phe)) mutations leading to transcript degradation and classic MKS features (PMID:23349226). A long-read sequencing study confirmed compound heterozygosity including a splice donor variant c.929+1A>G and an exon 4 deletion in a third family (PMID:31663672). More recently, novel splice site variants c.583-1G>C and c.583-2_588delinsTCCTCCC were reported in a nonconsanguineous fetus with intrauterine death, expanding the allelic spectrum (PMID:37736303).

Overall, 4 unrelated probands across three families demonstrate autosomal recessive inheritance with biallelic loss-of-function and hypomorphic alleles (PMID:23349226; PMID:31663672; PMID:37736303). Variant classes include canonical splice site (e.g., c.583-1G>C), frameshift (p.Val70fs), nonsense (p.Gln127Ter) and missense (p.Val222Phe) changes.

Functional assays show that splice site variants cause exon skipping and reduced TMEM231 transcript levels by qRT-PCR, and immunofluorescence reveals near absence of primary cilia in patient kidney tissue (PMID:37736303). In the original MKS families, the splice mutation led to complete mutant transcript degradation in vitro, confirming loss-of-function as the disease mechanism (PMID:23349226).

No studies dispute this association; all reported variants segregate with disease in parental carriers, and functional data are concordant with the human phenotype. TMEM231 deficiency causes defective ciliogenesis through haploinsufficiency of essential ciliary proteins.

In summary, multiple independent families, segregation in carriers, and consistent functional studies yield a definitive gene–disease relationship between TMEM231 and Meckel syndrome. TMEM231 variant screening should be incorporated in prenatal and diagnostic panels for MKS.

References

• Journal of medical genetics • 2013 • Mutations in TMEM231 cause Meckel-Gruber syndrome. PMID:23349226
• Human Mutation • 2020 • Long-read nanopore sequencing resolves a TMEM231 gene conversion event causing Meckel-Gruber syndrome. PMID:31663672
• Frontiers in Genetics • 2023 • Identification of novel TMEM231 gene splice variants and pathological findings in a fetus with Meckel Syndrome. PMID:37736303

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