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A new set of clinical tools for physicians
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
Studies of multiple unrelated patients with the same rare phenotype have led to the discovery of the following associations between phenotypes and genes: Myhre syndrome and SMAD4; study of four families of Tunisian origin with autosomal recessive cerebellar ataxia, discovered a new gene, GBA2, was the cause; and four unrelated people with trismuspseudocamptodactyly syndrome, tropomysin.
Advances in our understanding of human spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Qing Wen, Elizabeth I. Tang, Tito Jesus, Bruno Silvestrini, C. Yan Cheng
Studies using genetic models in mice have identified a number of genes associated with different cellular events during spermiogenesis.86 These include acrosome biogenesis (e.g., Gopc [Golgi-associated PDZ and coiled-coil motif containing protein] and Gba2 [ß glucosidase 2]), flagella assembly (e.g., Tekt2 [Tektin 2], Tek4 [Tektin 4], Vdac3 [voltage-dependent anion channel 3]), energy metabolism for motility (e.g., Catsper1-4 [cation channel, sperm associated 1, 2, 3, and 4], Gapdhs [glyceraldehyde-3-phospahte dehydrogenase sperm-specific]), nuclear condensation (e.g., Tnp1, [transition protein 1], Tnp2, Prm1 [protamine 1] Prm2), and cytoplasm removal (e.g., Spem 1 [sperm maturation 1]). In this context, it is of interest to note that early stages of spermiogenesis are monitored with various checkpoints, perhaps up to step 8 spermatids in rodents. For instance, round spermatids with defects are usually removed from the epithelium, such as through the formation of multinucleated spermatids—a common feature of abnormal spermiogenesis87 that leads to infertility. It appears that these multinucleated spermatid cells are formed, at least in part, as a result of defects in intercellular bridges, such as observed after colchicine treatment,88 which is known to induce microtubule disassembly.89 Also, deletion of genes important to early spermiogenesis, such as genes pertinent to acrosome biogenesis (e.g., Gopc), leads to infertility.90 However, a similar quality control mechanism is absent in late spermiogenesis because deletion of late spermatid-associated genes (e.g., Catsper1-4, Spem 1) in mice fail to affect testis weights, and sperm counts are normal and development of defective late spermatids continue to proceed to spermiation even though abnormal sperms are found in these mice.86 At least spermatids from these mice could be used for ICSI to obtain successful pregnancy;however, the biology of spermiogenesis in humans remains largely unexplored.
Transcriptional control and transcriptomic analysis of lipid metabolism in skin barrier formation and atopic dermatitis (AD)
Published in Expert Review of Proteomics, 2019
Nilika Bhattacharya, Gitali Ganguli-Indra, Arup K. Indra
Transcript level of glucosyl-ceramide synthase (Ugcg), involved in conversion of complex sphingolipids into glucosyl-ceramide showed a decrease by 0.4-fold at E18.5, whereas acid beta-glucosidase (Gba2), which is involved in the salvage pathway, also showed a reduction by 0.7-fold, 0.6-fold and 0.5-fold in the skin of null mice on day E16.5, E17.5 and E18.5, respectively, [23].
Hereditary spastic paraplegias: time for an objective case definition and a new nosology for neurogenetic disorders to facilitate biomarker/therapeutic studies
Published in Expert Review of Neurotherapeutics, 2019
Liena E. O. Elsayed, Isra Z. M. Eltazi, Ammar E. M. Ahmed, Giovanni Stevanin
Second, mutations in a causative gene can be associated with neurological signs that are the major clinical features of overlapping diseases. This phenomenon is sometimes inseparable from the above observation about one gene presenting with multiple allelic disorders. For example, hereditary ataxias (HA) and HSP represent the two extremes of the spectrum of spinocerebellar neurodegenerative disorders. HAs can sometimes be difficult to differentiate clinically from HSPs as cerebellar manifestations are present as part of their clinical presentation in more than 30 clinico-genetic SPG entities (Figure 2). The reverse is also frequent. This is well illustrated with mutations in GBA2 published either in patients with ataxia and pyramidal syndrome or in patients with HSP with ataxia [43,49]. Many HSP subtypes present with peripheral neuropathy (e.g.: SPG5A, SPG11, SPG17, SPG30, SPG31, SPG57, SPG70 and rarely, SPG3A) and there are genes that can account for multiple phenotypes. Along this continuum of disorders affecting the first and second motor neuron are genes like SPG11 (HSP, ALS, and Charcot-Marie-Tooth disease), ALS2 (PLS, ALS, HSP) or BICD2 (HSP, spinal muscular atrophy) [11]. Another example is leukodystrophy, a non-neurodegenerative group of disorders. Although leukodystrophy is classified as a differential diagnosis of HSP that should be excluded in the early steps of clinico-genetic investigations, white matter abnormalities are described as a complicating feature for at least 28 HSP subtypes, making the distinction between these differential diagnoses a real challenge. Consequently, there are numerous causative genes that are located in the overlap zone, with related clinical scenarios. Examples of genes located in overlap zones are illustrated in Figure 2. These genes are classified as being related to HSP, HA, leukodystrophy, neurodegeneration with brain iron accumulation (NBIA), parkinsonism, PLS and ALS, cerebral palsy spastic quadriplegia (CPSQ), hereditary dystonia, mental retardation, peripheral neuropathy (PN) and even some inborn errors of metabolism (IEM) or neuro-development disorders. Clearly not all the above-mentioned categories are neurodegenerative, as exemplified by some of the overlapping metabolic disorders: e.g. leukodystrophy and IEM.