Unraveling the Membrane Topology of TMEM151A: A Step Towards Understanding its Cellular Role.

Transmembrane protein 151A (TMEM151A) has been identified as a causative gene for paroxysmal kinesigenic dyskinesia, though its molecular function remains almost completely unknown. Understanding the membrane topology of transmembrane proteins is crucial for elucidating their functions and possible interacting partners. In this study, we utilized molecular dynamics simulations, immunocytochemistry, and electron microscopy to define the topology of TMEM151A.

Case Report: Novel biallelic moderately damaging variants in in a patient with cerebellar dysplasia.

Rotatin, encoded by the gene, is a centrosomal protein with multiple, emerging functions, including left-right specification, ciliogenesis, and neuronal migration. Recessive variants in are associated with a neurodevelopmental disorder with microcephaly and malformations of cortical development known as "Microcephaly, short stature, and polymicrogyria with seizures" (MSSP, MIM #614833). Affected individuals show a wide spectrum of clinical manifestations like intellectual disability, poor/absent speech, short stature, microcephaly, and congenital malformations.

Missense mutations in the membrane domain of PRRT2 affect its interaction with Nav1.2 voltage-gated sodium channels.

PRRT2 is a neuronal protein that controls neuronal excitability and network stability by modulating voltage-gated Na channel (Nav). PRRT2 pathogenic variants cause pleiotropic syndromes including epilepsy, paroxysmal kinesigenic dyskinesia and episodic ataxia attributable to loss-of-function pathogenetic mechanism. Based on the evidence that the transmembrane domain of PRRT2 interacts with Nav1.

The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na channels.

Proline-rich transmembrane protein 2 (PRRT2) is the single causative gene for pleiotropic paroxysmal syndromes, including epilepsy, kinesigenic dyskinesia, episodic ataxia, and migraine. PRRT2 is a neuron-specific type-2 membrane protein with a COOH-terminal intramembrane domain and a long proline-rich NH-terminal cytoplasmic region. A large array of experimental data indicates that PRRT2 is a neuron stability gene that negatively controls intrinsic excitability by regulating surface membrane localization and biophysical properties of voltage-dependent Na channels Nav1.