A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia

IMPORTANCE: Olmsted syndrome (OS) is a rare keratinizing disorder characterized by excessive epidermal thickening of the palms and soles, with clinical and genetic heterogeneity. Approximately 50 cases have been reported, with the molecular basis described in only 9. Recently, TRPV3 (transient receptor potential vanilloid 3) mutations were identified in autosomal-dominant OS in 7 sporadic cases and 1 familial case, whereas an MBTPS2 (membrane-bound transcription factor protease, site 2) mutation was reported in X-linked recessive OS. We report a new sporadic case of severe, atypical OS and its underlying genetic basis. OBSERVATIONS: Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia. Whole exome sequencing of patient DNA identified a novel de novo heterozygous missense mutation within TRPV3, p.Leu673Phe, predicted to be damaging. CONCLUSIONS AND RELEVANCE: This case study further implicates TRPV3 in OS pathogenesis. In addition, previous reports of OS have not described erythromelalgia as a clinical feature. Its occurrence in our patient could be a chance event, but, if associated with OS, the features of erythromelalgia may expand the phenotypic spectrum of this rare syndrome. Copyright 2014 American Medical Association. All rights reserved

Bifidobacterium longum subsp. iuvenis subsp. nov., a novel subspecies isolated from the faeces of weaning infants

The species Bifidobacterium longum currently comprises four subspecies: B. longum subsp. longum, B. longum subsp. infantis, B. longum subsp. suis and B. longum subsp. suillum. Recently, several studies on B. longum suggested the presence of a separate clade containing four strains isolated from infants and one from rhesus macaque. These strains shared a phylogenetic similarity to B. longum subsp. suis DSM 20210T and B. longum subsp. suillum JCM1995T [average nucleotide identity (ANI) of 98.1%) while showed an ANI of 96.5% with both B. longum subsp. infantis and B. longum subsp. longum. The current work describes five novel additional B. longum strains isolated from Bangladeshi weaning infants and demonstrates their common phylogenetic origin with those of the previously proposed separated clade. Based on polyphasic taxonomic approach comprising loci multilocus sequence analysis and whole genome multilocus sequence typing, all ten examined strains have been confirmed as a distinct lineage within the species B. longum with B. longum subsp. suis and B. longum subsp. suillum as closest subspecies. Interestingly, these strains are present in weaning infants and primates as opposed to their closest relatives which have been typically isolated from pig and calves. These strains, similarly to B. longum subsp. infantis, show a common capacity to metabolize the human milk oligosaccharide 3-fucosyllactose. Moreover, they harbour a riboflavin synthesis operon, which differentiate them from their closest subspecies, B. longum subsp. suis and B. longum subsp. suillum. Based on the consistent results from genotypical, ecological and phenotypical analyses, a novel subspecies with the name Bifidobacterium longum subsp. iuvenis, with type strain NCC 5000T (=LMG 32752T =CCOS 2034T ), is proposed

The Pleiotropic Effects of Carbohydrate-Mediated Growth Rate Modifications in Bifidobacterium longum NCC 2705

Bifidobacteria are saccharolytic bacteria that are able to metabolize a relatively large range of carbohydrates through their unique central carbon metabolism known as the “bifid-shunt”. Carbohydrates have been shown to modulate the growth rate of bifidobacteria, but unlike for other genera (e.g., E. coli or L. lactis), the impact it may have on the overall physiology of the bacteria has not been studied in detail to date. Using glucose and galactose as model substrates in Bifidobacterium longum NCC 2705, we established that the strain displayed fast and slow growth rates on those carbohydrates, respectively. We show that these differential growth conditions are accompanied by global transcriptional changes and adjustments of central carbon fluxes. In addition, when grown on galactose, NCC 2705 cells were significantly smaller, exhibited an expanded capacity to import and metabolized different sugars and displayed an increased acid-stress resistance, a phenotypic signature associated with generalized fitness. We predict that part of the observed adaptation is regulated by the previously described bifidobacterial global transcriptional regulator AraQ, which we propose to reflect a catabolite-repression-like response in B. longum. With this manuscript, we demonstrate that not only growth rate but also various physiological characteristics of B. longum NCC 2705 are responsive to the carbon source used for growth, which is relevant in the context of its lifestyle in the human infant gut where galactose-containing oligosaccharides are prominent

Longitudinal Human Milk miRNA Composition over the First 3 mo of Lactation in a Cohort of Healthy Mothers Delivering Term Infants

International audienceABSTRACT Background MicroRNAs (miRNAs) are small noncoding RNAs involved in posttranscriptional regulation. miRNAs can be secreted and found in many body fluids, and although they are particularly abundant in breastmilk, their functions remain elusive. Human milk (HM) miRNAs start to raise considerable interest, but a comprehensive understanding of the repertoire and expression profiles along lactation has not been well characterized. Objectives This study aimed to characterize the longitudinal profile of HM miRNA between the second week and third month postpartum. Methods We used a new sensitive technology to measure HM miRNAs in a cohort of 44 French mothers [mean ± SD age: 31 ± 3.5; BMI (in kg/m2) 21.8 ± 2.3] who delivered at term and provided HM samples at 3 time points (17 ± 3 d, 60 ± 3 d, and 90 ± 3 d) during follow-up visits. Results We detected 685 miRNAs, of which 35 showed a high and stable expression along the lactation period analyzed. We also described for the first time a set of 11 miRNAs with a dynamic expression profile. To gain insight into the potential functional relevance of this set of miRNAs, we selected miR-3126 and miR-3184 to treat undifferentiated Caco-2 human intestinal cells and then assessed differentially expressed genes and modulation of related biological pathways. Conclusions Overall, our study provides new insights into HM miRNA composition and, to our knowledge, the first description of its longitudinal dynamics in mothers who delivered at term. Our in vitro results obtained in undifferentiated Caco-2 human intestinal cells transfected with HM miRNAs also provide further support to the hypothesized mother-to-neonate signaling role of HM miRNAs. This trial was registered at clinicaltrials.gov as NCT01894893

<i>Bifidobacterium longum</i> subsp. iuvenis subsp. nov., a novel subspecies isolated from the faeces of weaning infants

Supplementary material for 'Bifidobacterium longum subsp. iuvenis subsp. nov., a novel subspecies isolated from the faeces of weaning infants', a published in International Journal of Systematic and Evolutionary Microbiology</p

Contribution of genetic ancestry and polygenic risk score in meeting vitamin B12 needs in healthy Brazilian children and adolescents

Abstract Polymorphisms in genes related to the metabolism of vitamin B12 haven’t been examined in a Brazilian population. To (a) determine the correlation between the local genetic ancestry components and vitamin B12 levels using ninety B12-related genes; (b) determine associations between these genes and their SNPs with vitamin B12 levels; (c) determine a polygenic risk score (PRS) using significant variants. This cross-sectional study included 168 children and adolescents, aged 9–13 years old. Total cobalamin was measured in plasma. Genotyping arrays and whole exome data were combined to yield ~ 7000 SNPs in 90 genes related to vitamin B12. The Efficient Local Ancestry Inference was used to estimate local ancestry for African (AFR), Native American, and European (EUR). The association between the genotypes and vitamin B12 levels were determined with generalized estimating equation. Vitamin B12 levels were driven by positive (EUR) and negative (AFR, AMR) correlations with genetic ancestry. A set of 36 variants were used to create a PRS that explained 42% of vitamin level variation. Vitamin B12 levels are influenced by genetic ancestry and a PRS explained almost 50% of the variation in plasma cobalamin in Brazilian children and adolescents

KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes

KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathie