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Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
A number of mutations in CYP17A1 are linked to 17α-hydroxylase deficiency, 17α-hydroxylase/17,20-lyase deficiency, pseudohermaphroditism, and adrenal hyperplasia type 5 (Dhir et al. 2009; Keskin et al. 2015; Kim et al. 2014; Krone and Arlt 2009; Rubtsov et al. 2015; Sahakitrungruang et al. 2009; Zhang et al. 2015). Lack of lyase activity can cause pseudohermaphroditism. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses, and short adult stature. SNPs in the coding region are the most common mutations observed in CYP17A1. Other mutations include a frameshift and premature stop codon attributed to a 2-bp deletion, changing the C-terminal 28 amino acids owing to a 4-bp duplication, and a 5′-splice site mutation. Some studies have reported that CYP17A1 loses its 17,20-lyase activity but not the 17-hydroxylation in patients presenting with symptoms owing to the change in Arg346Ala and Phe417Cys. The mutation at Thr306, which may involve protonation of Fe–OO− or O–O cleavage, affects the 17α-hydroxylation but not the lyase activity.
Neurofibromatosis 2
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
Standard mutation techniques, such as single-strand conformational polymorphism analysis or denaturing gradient gel electrophoresis, detect 35–66% of pathogenic mutations. The majority of these mutations are protein-truncating mutations (frameshift or nonsense mutations) and lead to a smaller and probably non-functional protein product. C > T transitions causing nonsense mutations are the most common mutations in the NF2 gene. Genotype-phenotype correlation studies have found that missense mutations (which result in a complete protein product) and large deletions (which result in no protein product) each cause predominantly mild phenotypes.10–13 Patients with splice-site mutations have variable clinical manifestations. The more severe phenotype in patients with protein-truncating mutations may be due to a dominant negative effect, with mutant protein dimerizing with the normal product, leaving less wild type protein for tumour suppression. This is supported by a positional effect of mutations (particularly for meningiomas with more severe disease associated with mutations in exons 1–4 and mild disease in the last two exons with mutations).13
Metachromatic leukodystrophy
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The gene for ASA is on chromosome 22 at q13 [15, 78–80]. The saposin B gene is on chromosome 10 [81, 82]. The ASA gene consists of eight exons in a small 3.2-kb coding area [83]; the mRNA is 2.1 kb. A large number of mutations has been found for ASA [17, 84, 85]. A common polymorphism leads to an enzyme with perfectly normal activity and a threonine to serine change in exon 7 [17]. In late infantile MLD, the mutant alleles are sometimes referred to as I-type mutations [17]. More often, these are now referred to as null alleles, which code for no enzyme activity. Two splice-site mutations have been identified that lead to this phenotype. They include the G609A transition that destroys the splice donor site of exon 2 by changing the exon–intron boundary from AGgt to AGat [17]. This common mutation in Europeans has also been seen in Arabs. Another was a G2195A transition at the splice-recognition site between exon 7 and the next intron [86]. In addition, an 11-bp deletion in exon 8, which causes a frameshift, was also found in this phenotype [87]. Point mutations have also been found in this phenotype, including a glycine 99 to aspartic acid change in exon 2 [88], common in Japan, and a glycine 245 to arginine change in exon 4 [89]. Other common mutations among Europeans are P426L [17] and I79S [84]. Mutations such as the G-to-A transition in exon 2 which results in a change from glycine 99 to aspartic acid [90] and the proline 426 change to leucine have been referred to as type A mutations and in the homozygous situation lead to adult-onset MLD. They are now referred to as R alleles and they code for some residual activity. In 26 patients in Italy [91], the c.459+1G>A mutation was found in 19 of 52 alleles (36.5%). There were ten rare mutations and eight newly found. By 2016, 200 mutations in the ASA gene have been recognized [92], the majority single point mutations leading to missense. There has been a clustering of mutations around exon 2 and 5. The most common alleles were c.465+1G>A, c.1283C>T, and c.542T>G. In a report of 16 Saudi patients with MLD, seven patients had ASA-deficiency, and four had sphingolipid activator deficiency. The latter four were homozygous for a g.722G>C transversion which led to a p.C241S previously reported mutation [93] and four have sphingolipid. Compound heterozygosity for the mutation (p.G99D and p.T409I0) was found in a Japanese female with behavioral abnormalities [94]. Nine pathogenic mutations were found in 13 Indian patients (65 percent), five of them novel. The most common mutation was c.459+16>A [95]. Compounds of A- and I-type mutations have been found in juvenile-onset patients [17]. In a Korean boy who could not walk at 12 months and died at nine years, a novel splicing mutation (c.1101+1G>T) in intron 6 was found on one allele, as well as a missense mutation in exon 2 (c.296G>A; p.Gly99Asp) [96].
The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS)
Published in Immunological Investigations, 2022
Saba Fekrvand, Samaneh Delavari, Zahra Chavoshzadeh, Roya Sherkat, Seyed Alireza Mahdaviani, Mahnaz Sadeghi Shabestari, Gholamreza Azizi, Mohammad Taghi Arzanian, Bibi Shahin Shamsian, Shabnam Eskandarzadeh, Narges Eslami, William Rae, Antonio Condino-Neto, Javad Mohammadi, Hassan Abolhassani, Reza Yazdani, Asghar Aghamohammadi
The other less reported mutation is a missense mutation affecting the inter-SH2 domain (c.1692 C > G p. N564K) (Elkaim et al. 2016; Wentink et al. 2017). In the current study, we found four novel mutations that are three splice site mutations: c.336 + 1 G > A and c.336 + 2 T > G with autosomal dominant inheritance pattern affecting the breakpoint cluster region homology domain (BH), c.1020–8 C > G with autosomal recessive inheritance pattern affecting the N-SH2 domain as well as a missense mutation (c.1558 T > G) with autosomal dominant inheritance pattern affecting the inter-SH2 domain. Our findings indicate that in APDS patients, other domains of PIK3CD and PIK3R1 could be affected as well. Increasing our knowledge about APDS with proper diagnostic criteria could lead to earlier diagnosis of the patients and conducting molecular analysis in the affected patients could help to better understand the probable correlations between genetic mutations and disease severity, suggesting the timely application of the appropriate treatment.
Atypical Presentation of Sengers Syndrome: A Novel Mutation Revealed with Postmortem Genetic Testing
Published in Fetal and Pediatric Pathology, 2020
Naz Guleray, Can Kosukcu, Zihni Ekim Taskiran, Pelin Ozlem Simsek Kiper, Gulen Eda Utine, Safak Gucer, Aysegul Tokatli, Koray Boduroglu, Mehmet Alikasifoglu
The clinical course of Sengers syndrome varies from lethality in the neonatal period to a more benign course with longer survival with patients surviving into the fourth decade (10,11,19). The present patient had severe hypotonia and episodes of elevated serum lactate levels. The clinical course of the present patient was not quite suggestive of Sengers syndrome due to the lack of detectable cataracts and clinical cardiomyopathy. The molecular pathophysiology leading to variable expression in Sengers syndrome is still unknown. Homozygous nonsense mutations mostly lead to infantile form whereas nonsense mutations in a compound heterozygous state with at least one splice site variant or a start codon mutation usually cause a milder disease [12]. A 12-year-old patient with milder clinical findings harboring a splice site mutation in a compound heterozygous state with a frameshift mutation in the same position as in our patient provides an additional evidence for this finding [12]. The location and positional effects of the variants in AGK may further contribute to variable expression such as the variants situated in conserved C-terminal region lead to a more severe form as was observed in our patient [20] (Figure 3).
C syndrome - what do we know and what could the future hold?
Published in Expert Opinion on Orphan Drugs, 2019
Roser Urreizti, Daniel Grinberg, Susanna Balcells
Recent studies have identified two heterozygous mutations in the IFT140 gene in one patient diagnosed as OCS [33]. Both mutations would lead to the loss of the functional protein (initiation codon loss and splice site mutation). This gene is associated with short-rib thoracic dysplasia 9 with or without polydactyly (SRTD9; MIM # 266,920), a ciliopathy associated with skeletal and renal dysplasia, retinal pigmentary dystrophy and cerebellar ataxia. Polydactyly is also a common trait for these patients. These authors suggested that many of the OCS symptoms overlap with those of a cilliopathy, including dysplasia of kidneys, liver and pancreas with cystic changes, as well as some of the skeletal anomalies observed in some OCS patients, and highlight that retinitis pigmentosa, together with Caroli’s syndrome and renal failure, was also previously described in another OCS patient [24].