CABP4 – Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

CACBP4 encodes neuronal calcium-binding protein 4, a key regulator of Cav1.4 L-type calcium channels in the brain. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by brief nocturnal motor seizures arising from the frontal lobe. A single four-generation Chinese pedigree comprising 27 members, including 11 individuals diagnosed with ADNFLE, was ascertained to identify the genetic cause ([PMID:29108277]). DNA samples were collected from 15 family members including seven affected and eight unaffected individuals ([PMID:29108277]).

Whole-exome sequencing in four affected relatives identified a novel heterozygous missense variant, c.464G>A (p.Gly155Asp), in CABP4 that was present in all seven affected individuals and absent from 300 unrelated controls ([PMID:29108277]). The variant localizes to the EF-hand 1 calcium-binding motif within the N-terminal lobe of CaBP4 and is predicted to be deleterious by PolyPhen-2 and SIFT ([PMID:29108277]). One young asymptomatic carrier suggests age-dependent penetrance.

In vitro functional assays using human neuronal cells demonstrated that c.464G>A (p.Gly155Asp) increases CABP4 mRNA levels but markedly reduces protein stability, as evidenced by RT-PCR and Western blot analyses ([PMID:35378956]). These findings indicate that the variant disrupts normal protein turnover and calcium buffering function in neurons.

A knock-in mouse model carrying the human p.Gly155Asp mutation was generated on a C57BL/6J background ([PMID:38840676]). Heterozygous CABP4G155D/+ mice showed altered regional protein expression and increased frequency of micro-excitatory post-synaptic currents in prefrontal cortex pyramidal neurons without overt seizure phenotypes, supporting a mechanistic role in neuronal hyperexcitability.

Together, the segregation of c.464G>A (p.Gly155Asp) in a multigenerational pedigree, absence in controls, deleterious in vitro effects on protein stability, and in vivo electrophysiological alterations provide moderate evidence for a pathogenic, haploinsufficiency-like mechanism. Functional studies concordantly demonstrate disrupted calcium signaling consistent with nocturnal frontal lobe seizure onset. Identification of CABP4 variants can guide genetic testing in ADNFLE and inform targeted therapeutic strategies.

References

• Oncotarget • 2017 • Exome sequencing identified a novel missense mutation c.464G>A (p.G155D) in Ca2+-binding protein 4 (CABP4) in a Chinese pedigree with autosomal dominant nocturnal frontal lobe epilepsy. PMID:29108277
• Translational pediatrics • 2022 • A novel missense creatine mutant of CaBP4, c.464G>A (p.G155D), associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), reduces the expression of CaBP4. PMID:35378956
• Translational pediatrics • 2024 • CABP4 mutation in mice shows alteration in protein expression level and neuron discharge frequency. PMID:38840676

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