Novel LIPA mutations in Mexican siblings with lysosomal acid lipase deficiency

We would like to thank Radhika Tripuraneni, MD, MPH, for critical reading of the manuscript, Angelica TorizOrtiz, MD, for ultrasound imaging, and the medical staff of the Endoscopy and Pathology Department of CMN “20 de Noviembre”, along with all the personnel involved in the care of the patients. This work was presented in abstract form at 2013’s National Week of Gastroenterology (Semana Nacional de Gastroenterologia de la AMG) in Veracruz, Mexico and at Ⅸ Congress of SLEIMPN in Medellín, Colombia.Peer reviewedPublisher PD

Mutations in the Gene DNAJC5 Cause Autosomal Dominant Kufs Disease in a Proportion of Cases: Study of the Parry Family and 8 Other Families

Background: The Neuronal Ceroid Lipofuscinoses (NCL) comprise at least nine progressive neurodegenerative genetic disorders. Kufs disease, an adult-onset form of NCL may be recessively or dominantly inherited. Our study aimed to identify genetic mutations associated with autosomal dominant Kufs disease (ADKD). Methodology and Principal Findings We have studied the family first reported with this phenotype in the 1970s, the Parry family. The proband had progressive psychiatric manifestations, seizures and cognitive decline starting in her mid 20s. Similarly affected relatives were observed in seven generations. Several of the affected individuals had post-mortem neuropathological brain study confirmatory for NCL disease. We conducted whole exome sequencing of three affected family members and identified a pLeu116del mutation in the gene DNAJC5, which segregated with the disease phenotype. An additional eight unrelated affected individuals with documented autosomal dominant or sporadic inheritance were studied. All had diagnostic confirmation with neuropathological studies of brain tissue. Among them we identified an additional individual with a p.Leu115Arg mutation in DNAJC5. In addition, a pAsn477Ser change in the neighboring gene PRPF6, a gene previously found to be associated with retinitis pigmentosa, segregated with the ADKD phenotype. Interestingly, two individuals of the Parry family did report visual impairment. Conclusions: Our study confirmed the recently reported association of DNAJC5 mutations with ADKD in two out of nine well-defined families. Sequence changes in PRPF6 have not been identified in other unrelated cases. The association of vision impairment with the expected PRPF6 dysfunction remains possible but would need further clinical studies in order to confirm the co-segregation of the visual impairment with this sequence change

Web-Based Behavioral Intervention Utilizing Narrative Persuasion for HIV Prevention Among Chinese Men Who Have Sex With Men (HeHe Talks Project): Intervention Development

Background: In the era of potent antiretroviral therapy, a high level of condomless anal intercourse continues to drive increases in HIV incidence in recent years among men who have sex with men. Effective behavior change strategies for promoting HIV-preventive behaviors are warranted. Narrative persuasion is a novel health communication approach that has demonstrated its persuasive advantages in overcoming resistance to counterattitudinal messages. The efficacy of narrative persuasion in promoting health behavior changes has been well documented, but critical research gaps exist for its application to HIV prevention. Objective: In this study, we aimed to (1) capitalize on narrative persuasion to design a web-based multisession intervention for reducing condomless anal intercourse among men who have sex with men in Hong Kong (the HeHe Talks Project) by following a systematic development process; and (2) describe the main components of the narrative intervention that potentially determine its persuasiveness. Methods: Persuasive themes and subtopics related to reducing condomless anal intercourse were initially proposed based on epidemiological evidence. The biographic narrative interview method was used to elicit firsthand experiential stories from a maximum variation sample of local men who have sex with men with diverse backgrounds and experiences related to HIV prevention; different types of role models were established accordingly. Framework analysis was used to aggregate the original quotations from narrators into collective narratives under 6 intervention themes. A dedicated website was finally developed for intervention delivery. Results: A series of video-based intervention messages in biographic narrative format (firsthand experiential stories shared by men who have sex with men) combined with topic-equivalent argumentative messages were produced and programmed into 6 intervention sessions. The 6-week intervention program can be automatically delivered and monitored online. Conclusions: We systematically created a web-based HIV prevention intervention derived from peer-generated stories. Strategies used to enhance the efficacy of the narrative intervention have been discussed within basic communication components. This paper describes the methods and experiences of the rigorous development of a narrative communication intervention for HIV prevention, which enables replication of the intervention in the future

Cell-by-cell dissection of phloem development links a maturation gradient to cell specialization

Publisher Copyright: Copyright © 2021 The Authors, some rights reserved;In the plant meristem, tissue-wide maturation gradients are coordinated with specialized cell networks to establish various developmental phases required for indeterminate growth. Here, we used single-cell transcriptomics to reconstruct the protophloem developmental trajectory from the birth of cell progenitors to terminal differentiation in the Arabidopsis thaliana root. PHLOEM EARLY DNA-BINDING-WITH-ONE-FINGER (PEAR) transcription factors mediate lineage bifurcation by activating guanosine triphosphatase signaling and prime a transcriptional differentiation program. This program is initially repressed by a meristem-wide gradient of PLETHORA transcription factors. Only the dissipation of PLETHORA gradient permits activation of the differentiation program that involves mutual inhibition of early versus late meristem regulators. Thus, for phloem development, broad maturation gradients interface with cell-type-specific transcriptional regulators to stage cellular differentiation.Peer reviewe

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB

An atypical case of neuronal ceroid lipofuscinosis with co-inheritance of a variably penetrant <it>POLG1</it> mutation

<p>Abstract</p> <p>Background</p> <p>The neuronal ceroid lipofuscinoses (NCLs, or Batten disease) comprise the most common Mendelian form of childhood-onset neurodegeneration, but the functions of the known underlying gene products remain poorly understood. The clinical heterogeneity of these disorders may shed light on genetic interactors that modify disease onset and progression.</p> <p>Case presentation</p> <p>We describe a proband with congenital hypotonia and an atypical form of infantile-onset, biopsy-proven NCL. Pathologic and molecular work-up of this patient identified <it>CLN5</it> mutations as well as a mutation―previously described as incompletely penetrant or a variant of unknown significance―in <it>POLG1</it>, a nuclear gene essential for maintenance of mitochondrial DNA (mtDNA) copy number. The congenital presentation of this patient is far earlier than that described for either CLN5 patients or affected carriers of the <it>POLG1</it> variant (c.1550 G > T, p.Gly517Val). Assessment of relative mtDNA copy number and mitochondrial membrane potential in the proband and control subjects suggested a pathogenic effect of the <it>POLG1</it> change as well as a possible functional interaction with <it>CLN5</it> mutations.</p> <p>Conclusions</p> <p>These findings suggest that an incompletely penetrant variant in <it>POLG1</it> may modify the clinical phenotype in a case of CLN5 and are consistent with emerging evidence of interactions between NCL-related genes and mitochondrial physiology.</p