Comparison of Two Therapeutic Approaches of Cerebellar Transcranial Direct Current Stimulation in a Sardinian Family Affected by Spinocerebellar Ataxia 38: a Clinical and Computerized 3D Gait Analysis Study.

Spinocerebellar ataxia 38 (SCA 38) is a very rare autosomal dominant inherited disorder caused by a mutation in ELOV5 gene, specifically expressed in cerebellar Purkinje cells, encoding an enzyme involved in the synthesis of fatty acids. Seven symptomatic SCA 38 patients of a Sardinian family were administered 15 sessions of cerebellar anodal transcranial direct current stimulation (tDCS) in a cross-over study, employing deltoid cerebellar-only (C-tDCS) and cerebello-spinal (CS-tDCS) cathodal montage. Clinical evaluation was performed at baseline (T0), after 15 sessions of tDCS (T1) and after 1 month of follow-up (T2).

p53 directs leader cell behavior, migration, and clearance during epithelial repair.

Epithelial cells migrate across wounds to repair injured tissue. Leader cells at the front of migrating sheets often drive this process. However, it is unclear how leaders emerge from an apparently homogeneous epithelial cell population.

Mig6 is a sensor of EGF receptor inactivation that directly activates c-Abl to induce apoptosis during epithelial homeostasis.

A fundamental aspect of epithelial homeostasis is the dependence on specific growth factors for cell survival, yet the underlying mechanisms remain obscure. We found an "inverse" mode of receptor tyrosine kinase signaling that directly links ErbB receptor inactivation to the induction of apoptosis. Upon ligand deprivation Mig6 dissociates from the ErbB receptor and binds to and activates the tyrosine kinase c-Abl to trigger p73-dependent apoptosis in mammary epithelial cells.

Efficacy and safety of quetiapine treatment for delusional parasitosis: experience in an elderly patient.

Delusional parasitosis is an unusual psychiatric disorder characterized by the false and persistent belief of being infested by parasites. Treatments include haloperidol, pimozide, and at present, olanzapine and risperidone. We report a case of delusional parasitosis in an elderly man, in which the treatment with low doses of quetiapine induced the complete remission of the syndrome, without any considerable side effects.

IRAK-M is involved in the pathogenesis of early-onset persistent asthma.

Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes.

Personality traits in Sardinia: testing founder population effects on trait means and variances.

Potential founder population effects on personality trait means and variances were examined in a large, genetically homogeneous sample (N=5,669) from the Ogliastra, an isolated region within Sardinia, Italy. The Italian version of the Revised NEO Personality Inventory showed good psychometric properties: Internal consistency reliabilities ranged from 0.80 to 0.

Heritability of cardiovascular and personality traits in 6,148 Sardinians.

In family studies, phenotypic similarities between relatives yield information on the overall contribution of genes to trait variation. Large samples are important for these family studies, especially when comparing heritability between subgroups such as young and old, or males and females. We recruited a cohort of 6,148 participants, aged 14-102 y, from four clustered towns in Sardinia.

Blepharophimosis, ptosis, and epicanthus inversus syndrome: clinical and molecular analysis of a case.

Blepharophimosis-ptosis-epicanthus inversus syndrome (OMIM #U10100) is a rare autosomal-dominant disorder in which an eyelid malformation is associated (type I) or not (type H) with premature ovarian failure in the affected female. It is invariably characterized by 4 major features: (1) bilaterally shortened horizontal palpebral fissure (blepharophimosis); (2) severe impairment of the superior palpebral levator (ptosis); (3) a vertical skin fold arising from the lower eyelid, which inserts medially in the upper lid (epicanthus inversus) and (4) an increased inner can-thal distance with a normal outer canthal distance (telecanthus). The mutations causing this disorder are found in the FOXL2 gene, a forkhead transcription factor, located in 3q23.

Foxl2 is required for commitment to ovary differentiation.

Genetic control of female sex differentiation from a bipotential gonad in mammals is poorly understood. We find that mouse XX gonads lacking the forkhead transcription factor Foxl2 form meiotic prophase oocytes, but then activate the genetic program for somatic testis determination. Pivotal Foxl2 action thus represses the male gene pathway at several stages of female gonadal differentiation.

Aging of oocyte, ovary, and human reproduction.

We review age-related changes in the ovary and their effect on female fertility, with particular emphasis on follicle formation, follicle dynamics, and oocyte quality. The evidence indicates that the developmental processes leading to follicle formation set the rules determining follicle quiescence and growth. This regulatory system is maintained until menopause and is directly affected in at least some models of premature ovarian failure (POF), most strikingly in the Foxl2 mouse knockout, a model of human POF with monogenic etiology (blepharophimosis/ptosis/epicanthus inversus syndrome).

FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences.

A translocation breakpoint 171 kb 5' of the transcription start of FOXL2 causes blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) and associated premature ovarian failure. The breakpoint falls within another gene, MRPS22, that has been sequenced in 500 kb of continuous DNA. MRPS22 encodes 20 exons and a number of alternative transcripts.

Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development.

FOXL2 mutations cause gonadal dysgenesis or premature ovarian failure (POF) in women, as well as eyelid/forehead dysmorphology in both sexes (the 'blepharophimosis-ptosis-epicanthus inversus syndrome', BPES). Here we report that mice lacking Foxl2 recapitulate relevant features of human BPES: males and females are small and show distinctive craniofacial morphology with upper eyelids absent. Furthermore, in mice as in humans, sterility is confined to females.

Genes and translocations involved in POF.

Changes at a single autosomal locus and many X-linked loci have been implicated in women with gonadal dysgenesis [premature ovarian failure (POF) with deficits in ovarian follicles]. For the chromosome 3 locus, a forkhead transcription factor gene (FOXL2) has been identified, in which lesions result in decreased follicles by haploinsufficiency. In contrast, sporadic X; autosomal translocations are distributed at many points on the X, but concentrate in a critical region on Xq.

Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling.

The type 1 Simpson-Golabi-Behmel overgrowth syndrome (SGBS1) is caused by loss-of-function mutations of the X-linked GPC3 gene encoding glypican-3, a cell-surface heparan sulfate proteoglycan that apparently plays a negative role in growth control by an unknown mechanism. Mice carrying a Gpc3 gene knockout exhibited several phenotypic features that resemble clinical hallmarks of SGBS1, including somatic overgrowth, renal dysplasia, accessory spleens, polydactyly, and placentomegaly. In Gpc3/DeltaH19 double mutants (lacking GPC3 and also carrying a deletion around the H19 gene region that causes bialellic expression of the closely linked Igf2 gene by imprint relaxation), the Gpc3-null phenotype was exacerbated, while additional SGBS1 features (omphalocele and skeletal defects) were manifested.

The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.

In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II.

Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28.

Linkage disequilibrium (LD), or the non-random association of alleles, is poorly understood in the human genome. Population genetic theory suggests that LD is determined by the age of the markers, population history, recombination rate, selection and genetic drift. Despite the uncertainties in determining the relative contributions of these factors, some groups have argued that LD is a simple function of distance between markers.

Jagged-1 mutation analysis in Italian Alagille syndrome patients.

Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities affecting the liver, heart, eyes, vertebrae, and craniofacial region. The Jagged-1 (JAG1) gene, which encodes a ligand of Notch, has recently been found mutated in AGS. In this study, mutation analysis of the JAG1 gene performed on 20 Italian AGS patients led to the identification of 15 different JAG1 mutations, including a large deletion of the 20p12 region, six frameshift, three nonsense, three splice-site, and two missense mutations.

Glypican 3 and glypican 4 are juxtaposed in Xq26.1.

Recently, we have shown that mutations in the X-linked glypican 3 (GPC3) gene cause the Simpson-Golabi-Behmel overgrowth syndrome (SGBS; ). The next centromeric gene detected is another glypican, glypican 4 (GPC4), with its 5' end 120763bp downstream of the 3' terminus of GPC3. One recovered GPC4 cDNA with an open reading frame of 1668nt encodes a putative protein containing three heparan sulfate glycosylation signals and the 14 signature cysteines of the glypican family.

DNA methylation in transcriptional repression of two differentially expressed X-linked genes, GPC3 and SYBL1.

Methylation of CpG islands is an established transcriptional repressive mechanism and is a feature of silencing in X chromosome inactivation. Housekeeping genes that are subject to X inactivation exhibit differential methylation of their CpG islands such that the inactive alleles are hypermethylated. In this report, we examine two contrasting X-linked genes with CpG islands for regulation by DNA methylation: SYBL1, a housekeeping gene in the Xq pseudoautosomal region, and GPC3, a tissue-specific gene in Xq26 that is implicated in the etiology of the Simpson-Golabi-Behmel overgrowth syndrome.