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α1-Antitrypsin deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The gene for α1-AT is located on chromosome 14 at position q32.1 [12, 52]. It is 12.2 kb in length and contains 4 exons in a 1434 bp coding region [51]. In classic PIZZ α1-AT deficiency, a single nucleotide substitution of adenine for guanine codes for a lysine instead of glutamic acid in the M protein (Table 107.1) [13, 53]. Oligonucleotide probes have been made which recognize the Z and M sequences and can be used for diagnosis. This is particularly important for prenatal diagnosis, because prior to their development prenatal diagnosis was available only through fetal blood sampling. In the S variant, a glutamic acid at position 264 is changed to valine. Null alleles represent a heterogeneous group of mutations in which a variety of different mechanisms lead to an identical phenotype [54]. Prenatal diagnosis has been carried out in two pregnancies at risk for the ZZ disease by oligonucleotide hybridization to DNA of cultured amniocytes [55]. Both fetuses were found to be MZ heterozygotes. Parental PI typing is essential for prenatal diagnosis to be sure both parents have the Z allele, and that there is no null or rare deficiency allele. Currently, the method of choice is to employ PCR amplification of exon 5 and detection of the Z mutation by oligonucleotide probes labeled with 32P [56] or with biotin [57].
Abnormal larval neuromuscular junction morphology and physiology in Drosophila prickle isoform mutants with known axonal transport defects and adult seizure behavior
Published in Journal of Neurogenetics, 2022
Atsushi Ueda, Tristan C. D. G. O’Harrow, Xiaomin Xing, Salleh Ehaideb, J. Robert Manak, Chun-Fang Wu
For the current studies, the pksple1 and pkpk1 alleles were introgressed into the control wild-type Oregon-R (OR) to eliminate background differences. First, the relevant prickle mutant flies were crossed with OR flies. The resulting F1 heterozygous flies were crossed together, and then the F2 flies were screened for homozygous flies indicated by the characteristic planar cell polarity phenotypes. These F2 homozygous mutant flies were backcrossed to the OR flies. This process was repeated 5 times. All these lines used in this study have been documented previously (Ehaideb et al., 2014). Briefly, pksple1 is characterized by creation of a stop codon in the first coding exon of the sple transcript isoform, while pkpk1 is characterized by insertion of a tirant DNA element into the first exon of the pk transcript isoform. Both alleles behave as null alleles in genetic tests (Gubb et al., 1999). Heterozygous mutants (pkpk1/+ & pksple1/+) were generated by crossing the homozygous pk mutant lines to OR. Similarly, heteroallelic mutants (pkpk1/pksple1) were generated by cross between the two homozygous mutant lines.
Unravelling the genetic architecture of autosomal recessive epilepsy in the genomic era
Published in Journal of Neurogenetics, 2018
Jeffrey D. Calhoun, Gemma L. Carvill
In addition to research driven studies, the rapid assimilation of WES clinical genetic testing for patients with epilepsy is facilitating the discovery of AR genes. Indeed, it is likely that in the future the vast majority of these novel genes will be identified as a result of clinical genetic testing. Despite these exciting advances, it still remains a challenge for many physicians and genetic counselor to interpret and counsel on variants of uncertain significance (VUS). To date, these are mostly reported by commercial genetic diagnostic testing companies when variants are homozygous and lead to null alleles. Many of these reports will be in genes that are good candidates for the disorder based on function, but will be present only in a single family. As in the research sphere the Matchmaker Exchange network and initiatives such as the Citizens United for Research in Epilepsy (CURE) sponsored Epilepsy Genetics Initiative (EGI) (see URLs) are useful resources for clinicians to identify additional patients with pathogenic variants in the same gene. The key to the success of these approaches lies in the widespread use of these exchanges and initiatives, and education of clinicians and genetic counselors on the advantages of using these tools.
Genotypic and phenotypic factors influencing the rate of progression in ABCA-4-related Stargardt disease
Published in Expert Review of Ophthalmology, 2021
Vincenzo Starace, Marco Battista, Maria Brambati, Matteo Pederzolli, Chiara Viganò, Alessandro Arrigo, Maria Vittoria Cicinelli, Francesco Bandello, Maurizio Battaglia Parodi
In general, deleterious variants are associated with aggressive progression of the disease, while missense mutations yield to milder phenotypes. For instance, patients harboring c.5882 G > A (p.G1961E) ABCA4 mutation have been characterized with a confined maculopathy, lower accumulation of lipofuscin, preservation of cone and rod function, and a long-term better visual prognosis[42]. By contrast, the genetic subsets characterized by null alleles have been associated with more severe and earlier onset of disease[43]. One particular ABCA4 variant (c.5461–10 T > C) has been related to faster electrophysiologic progression[41].