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!
The CHRNA1 gene encodes the alpha1 subunit of the fetal muscle nicotinic acetylcholine receptor (nAChR), essential for neuromuscular transmission and somite development. Nicotinic acetylcholine receptors mediate synaptic signaling, and loss of CHRNA1 function abolishes channel assembly. CHRNA1 is highly expressed in embryonic skeletal muscle and early somites. Biallelic disruption of CHRNA1 results in receptor deficiency and fetal akinesia. Phenotypically, this presents as lethal multiple pterygium syndrome (Lethal Multiple Pterygium Syndrome), characterized by intrauterine growth retardation, multiple pterygia, flexion contractures, edema, and hydrops fetalis (PMID:36092864; PMID:18252226).
Trio whole-exome sequencing in a Chinese family identified novel compound heterozygous variants in CHRNA1: c.1128delG (p.Pro377LeufsTer10) and c.505T>C (p.Trp169Arg) in a fetus with recurrent LMPS. The affected pregnancy exhibited increased nuchal translucency (HP:0010880), edema (HP:0000969), fetal neck cystoma, reduced movement, and joint contractures (HP:0001371) (PMID:36092864). Each parent was heterozygous for one variant, confirming autosomal recessive inheritance. No additional live affected relatives were reported. Both variants are absent from population databases and are predicted to truncate transmembrane domains critical for channel assembly.
A broader cohort analysis of acetylcholine receptor subunit genes in fetal akinesia deformation sequence disorders identified homozygous nonsense and splice-site CHRNA1 variants associated with lethality. Null alleles such as c.379A>T (p.Lys127Ter) and c.189+1G>A were observed in unrelated fetuses displaying cystic hygroma (HP:0000476) and hydrops fetalis (HP:0001789) (PMID:18252226). Mouse embryo expression studies localized Chrna1 transcripts to early somites and developing muscle, implicating early developmental defects beyond postnatal neuromuscular dysfunction (PMID:18252226). These data consolidate CHRNA1 loss-of-function as a mechanism for embryonic akinesia and pterygium formation.
Autosomal recessive inheritance is supported by parental segregation of distinct CHRNA1 alleles without manifestations in heterozygotes. Segregation analysis confirmed biallelic transmission in the Chinese family, and no heterozygous carriers exhibited anomalies. Reported CHRNA1 variant classes include frameshift, nonsense, and splice-site mutations, all consistent with complete loss of function rather than hypomorphic alleles. Collectively, this satisfies segregation criteria for recessive disorders and underscores the gene’s dosage sensitivity.
Functional embryonic models demonstrate that complete loss of alpha1 subunit disrupts nAChR assembly and neuromuscular signaling. In vitro knockout of Chrna1 in murine embryos recapitulates decreased somite-derived muscle movement and joint contractures. Rescue experiments restoring CHRNA1 expression in oocytes recover channel function, underscoring targetable pathways. This concordance between animal models and human phenotype supports a loss-of-function mechanism. No conflicting data on CHRNA1 and LMPS have been reported. Overall, functional results align with the severe prenatal phenotype.
In summary, biallelic CHRNA1 loss-of-function variants cause lethal multiple pterygium syndrome, marked by prenatal akinesia and pterygium formation. Genetic testing for CHRNA1 should be considered in fetuses with ultrasound anomalies of growth retardation, pterygia, and contractures. This association is supported by multiple unrelated cases, familial segregation, and mechanistic animal studies. Implementation of WES in prenatal diagnostics can accelerate etiologic clarification and counseling. Future research may assess potential therapeutic modulation of nAChR assembly in utero. Key take-home: CHRNA1 screening is clinically valuable for early diagnosis of LMPS and guiding reproductive decisions.
Gene–Disease AssociationModerate3 unrelated fetuses with biallelic CHRNA1 loss-of-function variants (compound heterozygous and homozygous) showing segregation and concordant phenotype Genetic EvidenceModerateIdentification of compound heterozygous (c.1128delG, c.505T>C) and homozygous nonsense CHRNA1 variants in 3 unrelated prenatal cases; familial segregation confirmed Functional EvidenceModerateMouse embryo expression and knockout models recapitulate fetal akinesia and joint contractures, supporting a loss-of-function mechanism |