Prader–Willi Syndrome: An Example of Genomic Imprinting
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
In 1989, molecular genetic methods and Southern hybridization of newly identified polymorphic DNA markers isolated from the 15q11–q13 chromosome region were reported by Nicholls et al. (14) in PWS individuals with normal appearing chromosomes and both chromosome 15s were from the mother. This phenomenon was termed maternal uniparental disomy 15 or UPD. Both members of the chromosome 15 pair were inherited from the mother as a result of nondisjunction or an error in the separation of the 15th chromosome pair in meiosis during egg production. One normal chromosome 15 was received from the father resulting in trisomy 15 (or three 15s) in the fetus. After fertilization, the father’s chromosome 15 is lost in the fetal cells during early pregnancy. If the trisomic 15 condition would have continued, a spontaneous miscarriage would have resulted. The loss of the father’s chromosome 15 in subsequent cells rescues the fetus. Chromosome abnormalities, specifically trisomy 15 and other trisomy and monosomy events, are common causes of spontaneous miscarriages. Approximately 50% of early miscarriages in the general population are due to chromosome problems.
Pathophysiology of Sleep-Disordered Breathing in Children and Neonates
Susmita Chowdhuri, M Safwan Badr, James A Rowley in Control of Breathing during Sleep, 2022
PWS is a congenital disorder typified by hypothalamic obesity, developmental delay, hypotonia, and hypogonadism. The vast majority of patients have abnormalities of chromosome 15 (84). Although patients with PWS do not have classic central hypoventilation, they are included here as physiological testing has shown abnormalities of ventilatory control. OSAS and REM-associated desaturation are seen commonly. Patients tend to have restrictive lung disease based on obesity and muscle weakness (85), which can explain the tendency to desaturate. Excessive daytime sleepiness is common, and it has not been established whether this is due to SDB or also to a CNS component. Patients appear more predisposed to REM-onset sleep, although published studies have not excluded confounding factors such as sleep deprivation or partial upper airway obstruction (86). Physiological studies have shown blunted hypercapnic ventilatory responses secondary to obesity; patients in whom weight has been controlled have a normal hypercapnic drive. However, the ventilatory response to hypoxia (87), as well as other tests of peripheral chemoreceptor function, show a marked decrease in peripheral chemoreceptor function (88). A unifying hypothesis, therefore, is that the abnormalities of ventilatory control are due to the central processing of chemoreceptor input. Interestingly, a recent study shows that baseline ventilation and ventilatory drive increase following growth hormone administration, despite an unchanged body mass index (89).
Muscle, Bone, and Skin Disorders
Victor A. Bernstam in Pocket Guide to GENE LEVEL DIAGNOSTICS in Clinical Practice, 2019
Advances in Marfan syndrome research include assignment of the defective gene to chromosome 15 at D15S45. Chromosome 15 also contains genes coding for the type I collagen receptor, chondroitin sulfate proteoglycan I core protein, and cardiac muscle X-actin, which could be viewed as candidate genes for the mutation in Marfan syndromea partial sequence of a candidate gene for the Marfan syndrome has been definedde novomissense mutations have been detected in the fibrillin gene in some Marfan syndrome casesDNA polymorphism in the fibrillin gene has been closely linked to sporadic cases of Marfan syndrome
Changes in symmetry during gait in adults with Prader-Willi syndrome
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2020
Veronica Cimolin, Massimiliano Pau, Nicola Cau, Bruno Leban, Micaela Porta, Paolo Capodaglio, Alessandro Sartorio, Graziano Grugni, Manuela Galli
The PWS patients, who were periodically hospitalized in the Istituto Auxologico Italiano (Piancavallo, Italy), underwent a 4-week multidisciplinary rehabilitation program during hospital stays. All participants presented the typical PWS clinical phenotype (Cassidy et al. 2012). The genetic analysis showed that 16 patients had an interstitial deletion of the proximal long arm of chromosome 15 (del15q11-q13). Uniparental maternal disomy for chromosome 15 (UPD15) was found in 4 subjects. Mild mental retardation was displayed in all participants however they were fully able to understand and complete the testing. In this respect, one inclusion criterion was to achieve a score higher than the cut-off value of 24 in the Italian version of the Mini Mental State Examination (MMSE). Exclusion criteria were the presence of cardiovascular, respiratory, neurologic or orthopaedic conditions limiting the walking ability. For the unaffected individuals, exclusion criteria were the existence of cardiorespiratory, neurological or musculoskeletal disorders. All of them exhibit normal flexibility and muscle strength and no evident gait abnormalities and were able to walk independently. They were recruited among the personnel (staff and students) of the University of Cagliari. The experimental protocol was carried out in accordance with the ethical standards of the institutes and the 1964 Helsinki declaration and its later amendments. The procedure was approved by the ethics committee of the Institutes. All participants and PWS caregivers signed an informed consent form before enrolment.
Cryptic partial insertion of the RARA gene into the PML gene without reciprocal RARA-PML fusion: a case report and review of literature
Published in Acta Oncologica, 2020
Waqas Mahmud, Rachel Brown, Lela Buckingham, Adrian Tira, Deborah A. Katz
In this karyotypically normal case, the PML-RARA fusion gene is present as indicated by the positive qRT-PCR results and FISH results. The rearrangement is complex, with intrachromosomal rearrangement of chromosome 15. Assessment of PML‑RARA formation, or variant RARA gene rearrangements by means of conventional karyotyping, FISH or qRT‑PCR, is required for the diagnosis of APL, however, diagnosis can be challenging in APL cases with cryptic PML-RARA rearrangements. While this cryptic insertion has rarely been reported and no prognostic significance has been clearly established, this patient responded well to APL-directed therapy including ATRA treatment. A prompt diagnosis and the administration of targeted therapies are essential to improve the outcome in patients with APL.
Prader-Willi syndrome and Angelman syndrome: Visualisation of the molecular pathways for two chromosomal disorders
Published in The World Journal of Biological Psychiatry, 2019
Friederike Ehrhart, Kelly J. M. Janssen, Susan L. Coort, Chris T. Evelo, Leopold M. G. Curfs
MKRN3 is the first gene in the PWS region at chromosome 15. It is involved in controlling the onset of puberty (Abreu et al. 2015). Figure 3 shows how MKRN3 inhibits expression of the gonadotropin-releasing hormone (GNRH1), either directly or via the neurokinin B (NKB) pathway (Navarro et al. 2011). This causes luteinizing hormone (LH) and follicle-stimulating hormone levels to decrease causing downstream effects, which are not displayed here. The exact mechanism by which MKRN3 inhibits either NKB or GNRH1 is unknown. If MKRN3 suffers from loss of function by either a mutation or a deletion, puberty occurs early in life (Abreu et al. 2015). In PWS patients, however, pubic and axillary hair may develop early or normally, but the other features of puberty occur late and incomplete or not at all (Cassidy and Schwartz 1998). With the information that is now known about MKRN3, there is no explanation that can be given for this result. Any hypotheses about involvement of distal regulators within the PWS region, DNA loops or microRNA remain speculative.
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