Relationship between Human Evolution and Neurally Mediated Syncope Disclosed by the Polymorphic Sites of the Adrenergic Receptor Gene α2B-AR

<div><p>The objective of this study was to clarify the effects of disease on neurally mediated syncope (NMS) during an acute stress reaction. We analyzed the mechanism of the molecular interaction and the polymorphisms of the alpha-2 adrenoreceptor (α2B-AR) gene as the potential psychiatric cause of incentive stress. We focused on the following three genotypes of the repeat polymorphism site at Glu 301–303 in the α2B-AR gene: Glu12/12, Glu12/9, and Glu9/9. On the basis of our clinical research, NMS is likely to occur in people with the Glu12/9 heterotype. To verify this, we assessed this relationship with the interaction of Gi protein and adenylate cyclase by <i>in silico</i> analysis of the Glu12/9 heterotype. By measuring the difference in the dissociation time of the Gi-α subunit twice, we found that the Glu12/9 heterotype suppressed the action of adenylate cyclase longer than the Glu homotypes. As this difference in the Glu repeat number effect is thought to be one of the causes of NMS, we investigated the evolutionary significance of the Glu repeat number. Glu8 was originally repeated in simians, while the Glu12 repeats occurred over time during the evolution of bipedalism in humans. Taken with the Glu12 numbers, NMS would likely become a defensive measure to prevent significant blood flow to the human brain.</p></div

Phylogenetic tree constructed by the unweighted pair group method method showing the complete mtDNA region (16,750 bp) of 3 <i>Homo sapiens sapiens</i> and 6 primates and suggesting the evolution of the Glu9 and Glu12 repeats in the α2B-AR gene.

<p>The variability of the Glu repeats increased during the evolution of early primates to humans. This development likely changed the role of vasoconstriction in blood pressure while in an upright position.</p

Binding energy of Gi α-subunit protein by <i>in silico</i> analysis.

<p>The receptor included in the Glu12 repeats can be released quickly from the β and γ subunits. The α subunit has a faster effect on adenylate cyclase signaling.</p

Alignment of the α2B-AR sequences for the Glu repeat sites.

<p>¹ Amino acids number may vary species to species.</p><p>Alignment of the α2B-AR sequences for the Glu repeat sites.</p

Helix wheel (a) and binding site of Glu9 (b) and Glu12 (c).

<p>The helix wheel is mostly unchanged functionally as Glu9 and Glu12 bind to the site in the adjoining position.</p

Phylogenetic tree constructed by the neighbor-joining method showing the complete mitochondrial DNA (mtDNA) region (16,750 bp) of <i>Homo sapiens sapiens</i> and <i>Homo sapiens neanderthalensis</i> and suggesting the evolution of the Glu12 repeats.

<p>On the basis of the differences in Glu12 frequency in the three groups, it is likely that most ancestors of modern-day Africans primarily had Glu12 repeats of the α2B-AR gene, and not Glu9 repeats.</p

Allele frequency of Glu9 and Glu12 in 281 Japanese subjects.

<p>Allele frequency of Glu9 and Glu12 in 281 Japanese subjects.</p

Detection of Hereditary 1,25-Hydroxyvitamin D-Resistant Rickets Caused by Uniparental Disomy of Chromosome 12 Using Genome-Wide Single Nucleotide Polymorphism Array

<div><p>Context</p><p>Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR) gene. No patients have been reported with uniparental disomy (UPD).</p><p>Objective</p><p>Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12.</p><p>Materials and Methods</p><p>A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of <i>VDR</i> was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array.</p><p>Results</p><p>The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father’s allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents) showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium.</p><p>Conclusions</p><p>This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.</p></div

Genome-wide SNP Array Indicating Complete Maternal Isodisomy of Chromosome 12.

<p>B allele frequencies of chromosome 12 in the proband, the mother, and the father are shown. Allele segregation in the proband comprised AA (4,154 SNPs) and BB (4,742 SNPs) homozygotes only, and loss of heterozygosity (AB; 0 SNP). The parental allele segregation of chromosome 12 showed a heterozygous pattern. All other chromosomes had normal homo/heterozygous patterns. In the diagram for the proband, the pink spots (1,514 SNPs) represent SNPs identified as maternal, with no evidence of paternal SNPs (which would be blue).</p

After Treatment with High-dose Oral Calcium Supplementation.

<p>(A) Treatment course and laboratory data are shown. (B) Bone roentgenogram at 3 years and 8 months of age, showing markedly improved signs of rickets.</p