NALCN Dysfunction as a Cause of Disordered Respiratory Rhythm With Central Apnea

Abstract

The sodium leak channel nonselective protein (NALCN) is a regulator of the pacemaker neurons that are responsible for rhythmic behavior (including respiration), maintaining the resting membrane potential, and are required for action potential production. -null mice show early death associated with disrupted respiratory rhythms, characterized by frequent and profound apneas. We report 3 children (2 siblings) with compound heterozygous mutations in associated with developmental impairment, hypotonia, and central sleep-disordered breathing causing apneas. Supplemental oxygen normalized the respiratory rhythm. mutations have been previously reported to cause severe hypotonia, speech impairment, and cognitive delay as well as infantile neuroaxonal dystrophy and facial dysmorphism. Nonsynonymous changes in the 2 affected extracellular loops may be responsible for the deleterious effect on the stability of the respiratory rhythm. Although oxygen is known to be a stabilizer of respiratory rhythm in central apnea in children, its role in NALCN dysfunction requires further investigation.

Familial Sleep Disorders in Unknown Genetic Syndrome

“…Two of these studies also described dysrhythmic breathing. 12 In our cases, WES did not show any mutations of these two suspected loci, however, a different genetic background could be involved and the absence of mutations in those specific loci does not fully exclude the presence of a different form of complicated congenital central hypoventilation. Unfortunately, the lack of an underlying genetic pathogenic variant impeded the prompt scheduling of appropriate clinical investigations.…”

Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex

“…Notably, it is reported that mutation of R1094Q, which locates on the interface between FAM155A, domain III and domain IV ( Fig. 2e), leads to disordered respiratory rhythm with central apnea (Campbell et al, 2018), suggesting the importance of these inter-subunit interactions.…”

“…The structure of NALCN allowed us to locate all of the reported missense mutations identified in human diseases and model animals ( Fig. 1e, f) (Al-Sayed et al, 2013;Aoyagi et al, 2015;Campbell et al, 2018;Chong et al, 2015;Fukai et al, 2016;Funato et al, 2016;Karakaya et al, 2016;Lozic et al, 2016;Sivaraman et al, 2016;Vivero et al, 2017;Wang et al, 2016;Yeh et al, 2008).…”

Clinical and genetic characteristics of the syndrome of contractures of the limbs and face, hypothony and psychomotor retardation (OMIM: 616 266), caused by mutations in the NALCN gene

“…Эти данные согласуются с результатами других исследователей. Как показано на модельных организмах с мутациями в гене NALCN, дыхательные расстройства не являются следствием иммунодефицита, а в значительной степени обусловлены нарушением иннервации межреберных мышц и диафрагмы, участвующих в акте дыхания [14]. К настоящему времени физиологическая роль белка NALCN изучена недостаточно, однако он обнаружен почти у всех видов организмов и не имеет ортологов [15].…”