Therefore, we examined AKR1B1 gene expression in human fetal adrenals, adrenocortical cell line, and tumors and compared the results with the expression of steroidogenic genes (StAR and CYP11A) and regulators of adrenal cortex development [steroidogenic factor-1 (SF-1) and dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX1)].
The MOL1592 family included three affected subjects with crystalline retinopathy, skin ichthyosis, short stature and congenital adrenal hypoplasia, and were found to harbour a homozygous nonsense mutation (c.682C>T, p.Arg228Cys) in ALDH3A2, reported to cause Sjögren-Larsson syndrome (SLS).
Dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1 (DAX-1) inhibits SF-1-mediated induction of MIS and other steroidogenic genes, whereas Wilms' tumor suppressor gene (WT1) augments SF-1-mediated MIS expression.
Genes currently recognized to be involved include KAL-1 (associated with X-linked Kallmann Syndrome), gonadotropin-releasing hormone (GnRH) receptor, gonadotropins, pituitary transcription factors (HESX1, LHX3, and PROP-1), orphan nuclear receptors (DAX-1, associated with X-linked adrenal hypoplasia congenital, and SF-1), and three genes also associated with obesity (leptin, leptin receptor, and prohormone convertase 1 [ PC1]).
Although no mutations were detected in the FHM1 CACNA1A and FHM2 ATP1A2 genes in sporadic AHC patients, a mutation was found in the FHM2ATP1A2 gene in a family with AHC.
We report a novel ATP1A2 mutation in a kindred with features that bridge the phenotypic spectrum between AHC and FHM syndromes, supporting a possible common pathogenesis in a subset of such cases.
A de novo heterozygous missense mutation (c.2401G>A; p.D801N) was identified in exon 17 of ATP1A3 gene and this is one of the hotspot mutations found in AHC patients.
Autosomal dominant mutations in the human ATP1A3 gene encoding the neuron-specific Na(+)/K(+)-ATPase α3 isoform cause different neurological diseases, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) with overlapping symptoms, including hemiplegia, dystonia, ataxia, hyperactivity, epileptic seizures, and cognitive deficits.
The first aim of this study was to characterize a novel knock-in mouse model (Atp1a3<sup>E815K+/-</sup>, Matoub, Matb<sup>+/-</sup>) containing the E815K mutation of the Atp1a3 gene recognized as causing the most severe and second most common phenotype of AHC with increased morbidity and mortality as compared to other mutations.
Mutations in ATP1A3 are involved in a large spectrum of neurological disorders, including rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), with recent descriptions of overlapping phenotypes.
Mutations in ATP1A3, the gene that encodes the α3 subunit of the Na(+)/K(+) ATPase, are the primary cause of alternating hemiplegia of childhood (AHC).
Besides their usefulness in clarifying the pathophysiology of the disease, prospective studies involving larger cohorts of ATP1A3 mutated AHC patients are needed to provide a rationale for testing other molecules.
Growing evidence suggests that AHC, RDP and CAPOS syndrome are part of a large and continuously expanding clinical spectrum and share some recurrent clinical features, such as abrupt-onset, asymmetric anatomical distribution and the presence of triggering factors, which are highly suggestive of ATP1A3 mutations.
ATP1A3, the gene encoding the α3-subunit of the Na(+) /K(+) -ATPase pump, has been involved in four clinical neurological entities: (1) alternating hemiplegia of childhood (AHC); (2) rapid-onset dystonia parkinsonism (RDP); (3) CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) syndrome; and (4) early infantile epileptic encephalopathy.
In summary, ATP1A3 is the major pathogenic gene of AHC in Chinese patients; mutations have distinctive molecular features that discriminate them from neutral variants and are correlated with phenotypes.
Mutations in ATP1A3 encoding the catalytic subunit of the Na/K-ATPase expressed in mammalian neurons cause alternating hemiplegia of childhood (AHC) as well as an expanding spectrum of other neurodevelopmental syndromes and neurological phenotypes.
In order to identify ATP1A3-related phenotypes not meeting the classical criteria for RDP or AHC we lowered the threshold for mutation analysis in clinical presentations resembling AHC or RDP.
We report a typical case of AHC harboring a de novo mutation in the ATP1A3 gene, together with a duplication and insertion in the SLC2A1 gene who exhibited marked clinical improvement following ketogenic diet.
Most ATP1A3 mutations in AHC lie within a cluster in or near transmembrane α-helix TM6, including I810N that is also found in the Myshkin mouse model of AHC.