スミス マーゲニス ショウコウグン ノ ニホンジン カンジャ ニオケル センショクタイ 17p11.2 ケッシツ リョウイキ ニオケル ブンシ イデンガクテキ カイセキ

Smith-Magenis syndrome (SMS) is a contiguous gene syndrome caused by an interstitial deletion of chromosome 17p11.2. The clinical SMS spectrums include short stature, brachydactyly, developmental delay, dysmorphic features, mental retardation, hyperactivity, self-injury, seizures, and sleep abnormalities (especially, reduced REM sleep). Here we attempted to define the minimum common deletion at 17p11.2 in 8 Japanese patients with SMS using molecular cytogenetic approaches, including a prophase fluorescence in situ hybridization (FISH) ordering system and a stretched DNA fiber FISH. Our precise deletion mapping constructed by FISH revealed that one patient with SMS showed a much smaller deletion at 17p11.2 as compared with the other 7 patients with SMS. LLGL1 and FLII, previously mapped within the SMS critical deletion, were mutually nested, and retained on both chromosomes 17 in two patients. ZNF179, a RING finger protein family gene, on the SMS critical region was deleted on one of the two homologues 17p11.2 in 6 out of 8 patients with SMS in the present study. ZNF179 is a neuronal gene mapped on the SMS critical deletion and seems to be one of the candidates most likely to be affected with an impairment of the CNS in SMS patients. However, ZNF179 was retained on both 17p11.2 in two SMS patients exhibiting clinical findings characteristic of SMS, suggesting that ZNF179 might not be associated with the neurobehavioral impairments in SMS. Furthermore, DNA fragments from the region at 17p11.2 contained highly repetitive sequences, probably including the low-copy repeats (LCRs) associated with the deletion/duplication mechanism through non-allelic homologous recombination in the patients with SMS.　Key words : Smith-Magenis syndrome, 17p11.2, deletion map, LLGL1, FLII, ZNF17

Conformal Invariance of the D-Particle Effective Action

It is shown that the effective theory of D-particles has conformal symmetry with field-dependent parameters. This is a consequence of the supersymmetry. The string coupling constant is not transformed in contrast with the recent proposal of generalized conformal symmtery by Jevicki et al. This conformal symmetry can also be generalized to other Dp-brane systems.Comment: 12 pages, LaTeX, typos corrected, one footnote and one note adde

An Associative and Noncommutative Product for the Low Energy Effective Theory of a D-Brane in Curved Backgrounds and Bi-Local Fields

We point out that when a D-brane is placed in an NS-NS B field background with non-vanishing field strength (H=dB) along the D-brane worldvolume, the coordinate of one end of the open string does not commute with that of the other in the low energy limit. The degrees of the freedom associated with both ends are not decoupled and accordingly, the effective action must be quite different from that of the ordinary noncommutative gauge theory for a constant B background. We construct an associative and noncommutative product which operates on the coordinates of both ends of the string and propose a new type of noncommutative gauge action for the low energy effective theory of a Dp-brane. This effective theory is bi-local and lives in twice as large dimensions (2D=2(p+1)) as in the H=0 case. When viewed as a theory in the D-dimensional space, this theory is non-local and we must force the two ends of the string to coincide. We will then propose a prescription for reducing this bi-local effective action to that in D dimensions and obtaining a local effective action.Comment: 23 pages, LaTeX2e, 1 figur

De Novo Mutations in GNAO1, Encoding a Gαo Subunit of Heterotrimeric G Proteins, Cause Epileptic Encephalopathy

Heterotrimeric G proteins, composed of α, β, and γ subunits, can transduce a variety of signals from seven-transmembrane-type receptors to intracellular effectors. By whole-exome sequencing and subsequent mutation screening, we identified de novo heterozygous mutations in GNAO1, which encodes a Gαo subunit of heterotrimeric G proteins, in four individuals with epileptic encephalopathy. Two of the affected individuals also showed involuntary movements. Somatic mosaicism (approximately 35% to 50% of cells, distributed across multiple cell types, harbored the mutation) was shown in one individual. By mapping the mutation onto three-dimensional models of the Gα subunit in three different complexed states, we found that the three mutants (c.521A>G [p.Asp174Gly], c.836T>A [p.Ile279Asn], and c.572_592del [p.Thr191_Phe197del]) are predicted to destabilize the Gα subunit fold. A fourth mutant (c.607G>A), in which the Gly203 residue located within the highly conserved switch II region is substituted to Arg, is predicted to impair GTP binding and/or activation of downstream effectors, although the p.Gly203Arg substitution might not interfere with Gα binding to G-protein-coupled receptors. Transient-expression experiments suggested that localization to the plasma membrane was variably impaired in the three putatively destabilized mutants. Electrophysiological analysis showed that Gαo-mediated inhibition of calcium currents by norepinephrine tended to be lower in three of the four Gαo mutants. These data suggest that aberrant Gαo signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements