A study on pathogenicity of TGM1 gene mutations in a collodion baby / 中华皮肤科杂志

Objective:To investigate the genetic etiology of a pedigree with autosomal recessive congenital ichthyosis.Methods:Whole-exome sequencing was performed in a collodion baby, and Sanger sequencing was conducted to verify gene mutations. The PolyPhen-2, PROVEAN and Mutation Taster softwares, as well as protein homology modeling methods, were used to predict effects of gene variants; real-time fluorescence-based quantitative PCR and Western blot analysis were performed to analyze the effect of mutations on allelic mRNA and protein expression.Results:Whole-exome sequencing and Sanger sequencing confirmed a mutation c.919C>T (p.Arg307Trp) in exon 6 and a mutation c.1019G>A (p.Gly340Glu) in exon 7 of the TGM1 gene in the infant, which were inherited from his mother and father respectively. Bioinformatics analysis suggested that both the two mutations were harmful to protein structures, which were further supported by protein homology modeling. In vitro experiments showed that there was no significant difference in the mRNA expression of the TGM1 gene between the 293T cells transfected with wild-type plasmids and those transfected with mutant plasmids containing the mutation c.919C>T or c.1019G>A ( t=1.97, 1.28, P=0.12, 0.27, respectively) , but the TGase1 protein expression significantly decreased in the 293T cells transfected with the mutant TGM1 plasmids. Conclusion:The mutations c.919C>T and c.1019G>A in the TGM1 gene may be the molecular genetic etiology of severe ichthyosis in the infant, and the missense amino acids encoded by the two mutations may affect the TGase1 protein function by destroying its structure.

[Analysis on the clinical and retinal imaging characteristics of autosomal recessive bestrophinopathy].

Objective: To study the clinical and imaging features of autosomal recessive bestrophinopathy (ARB). Methods: Retrospective study. The clinical and imaging data of 14 participants were analyzed in using autofluorescence (AF), fluorescein angiography (FA) and spectral-domain optical coherence tomography (SD-OCT). Ten patients were screened for mutations in BEST1 gene. Results: Retinopathy of ARB were shown as bilaterally and circularly distributed yellow subretinal deposits in the mid-peripheral and posterior retina, which was observed more clearly by AF and FA. The abnormalities were observed as hyperreflection between the sub-retinal pigment epithelium space as well as the subretinal space by SD-OCT imaging. All of the patients showed serous retinal detachment, and 4 of them were found to have intraretinal schisis. Other ocular complications include choroidal neovascularization (CNV) and angle closure glaucoma (ACG) were also found in the patients. Genetic examinations showed that the mutations are compound heterozygous in five patients, homozygous in one patient and heterozygous in only one of the rest 4 patients. Conclusions: The combination of clinical and retinal imaging data may facilitate the diagnosis of ARB. Physicians should be cautious of the vision-threatening complications of the disease. (Chin J Ophthalmol, 2018, 54: 263-269).

A novel NDUFS4 frameshift mutation causes Leigh disease in the Hutterite population.

Leigh disease is a progressive, infantile-onset, neurodegenerative disorder characterized by feeding difficulties, failure to thrive, hypotonia, seizures, and central respiratory compromise. Metabolic and neuroimaging investigations typically identify abnormalities consistent with a disorder of mitochondrial energy metabolism. Mutations in more than 35 genes affecting the mitochondrial respiratory chain encoded from both the nuclear and mitochondrial genomes have been associated with Leigh disease. The clinical presentations of five individuals of Hutterite descent with Leigh disease are described herein. An identity-by-descent mapping and candidate gene approach was used to identify a novel homozygous c.393dupA frameshift mutation in the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4) gene. The carrier frequency of this mutation was estimated in >1,300 Hutterite individuals to be 1 in 27. © 2017 Wiley Periodicals, Inc.

Current research in the genes and proteins related with Usher syndrome / 中华眼底病杂志

Usher syndrome (USH) is an autosomal recessive hereditary disease,characterized as retinitis pigmentosa and deafness.According to the severity of hearing loss,presence or absence of vestibular dysfunction,Usher syndrome is divided into 3 clinical subtypes..USH1,USH2 and USH3.Due to the genetically heterogeneous,it is important and valuable to find out the gene mutations in USH patients,which will be helpful to prenatal diagnosis,early intervention and gene therapy.Till now,the following 13 USH-related chromosomal loci were reported in the literature:USH1B,USH1C,USH1D (CDH23 gene),USH1F (PCDH15 gene),USH1G (SANS gene),USH1E,USH1H,USH1J and USH1K,USH2A,USH2C,USH2D and USH3 (CLRN1 gene).Ten out of all 13 loci have been located and identified.But more mechanisms should be further investigated,such as the relationship between the locus of gene mutations and clinical symptoms,how the modified protein structures and functions trigger clinical symptoms.

Plasma vitamin E and coenzyme Q10 levels and clinical significance in patients with autosomal recessive cerebellar ataxia / 中华神经科杂志

Objective To analyze plasma vitamin E and CoQ10 levels in patients with autosomal recessive cerebellar ataxia for finding the evidence of the related pathogenesis research and therapeutic strategies.Methods The plasma vitamin E and CoQ10 levels were detected by high performance liquid chromatography (HPLC) with diode array detector in 123 probands of autosomal recessive cerebellar ataxia pedigrees.Quantitation was performed using vitamin E and CoQ10 external standard and two 5-point calibration curve;clinical manifestations were analyzed simuhaneously.Results Vitamin E and CoQ10 levels of healthy subjects in the plasma were (8.77 ± 2.28) μg/ml and (1.31 ± 0.38) μg/ml,respectively;the plasma vitamin E and CoQ10 levels of patients were (5.61 ± 2.04) μg/ml and (0.79 ± 0.26) μg/ml,respectively,which were significantly lower than those in healthy controls (t =11.87,13.15;all P＜ 0.01).Clinical manifestations were characterized by cerebellar symptoms,and gait instability was usually the first recognized abnormality.Most of early onset occurred before the age of 25 years (111/123);dysarthria and abnormal eye movement were observed,with cerebellar atrophy on MRI;concomitant symptoms were also present.Conclusions HPLC analysis shows that the plasma vitamin E and CoQ10 levels of patients with autosomal recessive cerebellar ataxia are generally lower than those in the healthy controls.Several patients with significant reductions in these two levels have genetic defects.The combination of clinical phenotypes,biochemical indexes and genetic analyses will be helpful for the establishment of diagnosis and specific treatment.

Hiperplasia adrenal congênita por deficiência da 21-hidroxilase, forma clássica: estudo da freqüência em famílias de indivíduos afetados / Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic form: frequency evaluation of families with affected patients

OBJETIVOS: Analisar a freqüência de indivíduos afetados e das formas clínicas da doença, de acordo com o gênero e a taxa de consangüinidade, em famílias com hiperplasia adrenal congênita (HAC) por deficiência da enzima 21-hidroxilase, forma clássica (HAC-D21-OHC). MÉTODOS: A casuística foi composta por 58 famílias com 79 indivíduos afetados (67 vivos e 12 mortos) com pais normais e pelo menos um filho afetado vivo com diagnóstico comprovado da doença. A freqüência de indivíduos afetados foi avaliada pelas técnicas de Haldane e Hogben, com análise por seleção truncada. Também foram avaliadas a história parental de consangüinidade e a freqüência de homozigose de mutações no gene CYP21A2, bem como a forma clínica da doença e a distribuição por gênero. RESULTADOS: Dez famílias apresentaram história de consangüinidade entre os pais e mais cinco com homozigose no estudo molecular. A freqüência de indivíduos afetados nas irmandades avaliadas foi de 23,5 por cento, semelhante à esperada de 25 por cento; no entanto, com distribuição heterogênea. Quanto às formas clínicas, 56 (70 por cento) eram perdedores de sal (25M:31F) e 23 (30 por cento) virilizantes simples (10M:13F), não sendo observada diferença na distribuição entre os gêneros. CONCLUSÕES: Estes dados confirmam que a HAC-D21-OHC apresenta padrão de herança monogênica autossômica recessiva, com freqüência de 23,5 por cento na irmandade de indivíduos afetados, elevada taxa de consangüinidade e proporção semelhante entre os gêneros, porém com distribuição heterogênea no número de casos nas irmandades e predomínio da forma clínica perdedora de sal.

OBJECTIVE: To analyze the frequency of affected patients, rate of parental consanguinity and clinical forms of the disease, according to sex in families with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, classic form (CAH-21-OHD-C). METHODS: 58 families with 79 patients (67 alive and 12 dead) with non-affected parents and at least one affected live patient with an established diagnosis of the disease by molecular analysis were studied. The frequency of affected siblings was evaluated according to Haldane and Hogben techniques by truncated selection. Data about parental consanguinity, frequency of CYP21A2 homozygosis gene mutation, clinical form of the disease and sex distribution were also evaluated. RESULTS: Ten families had parental history of consanguinity and other five had homozygosis in the molecular analysis. The frequency of affected children in the kindred was 23.5 percent, similar to the 25 percent expected, but the sample showed a heterogeneous distribution. Among the clinical forms, 56 (70 percent) patients had the salt wasting form (25 males and 31 females) and 23 (30 percent) the simple virilizing one (10 males and 13 females) without difference in sex distribution. CONCLUSIONS: These data confirm that CAH-21-OHD-C has an autosomal recessive monogenic inheritance, with a high rate of consanguinity, similar distribution in both sexes, but it has a heterogeneous distribution of cases among the kindred with predominance of the salt wasting form.

Aposthia: a birth defect or normal quantitative recessive human genetic trait?

Aposthia [natural circumcision] is the condition of being born without a prepuce. Usually sporadic cases are reported in the medical literature. In this paper for the first time we present the genetic profile of 3 families with aposthia trait and discuss the possible genetics

Profile of major congenital malformations in neonates in Al-Jahra region of Kuwait

We investigated major congenital abnormalities in babies born in Al Jahra Hospital, Kuwait from January 2000 to December 2001. Of 7739 live and still births born over this period, 97 babies had major congenital malformations [12.5/1000 births]: 49 [50.6%] babies had multiple system malformations, while 48 [49.4%] had single system anomalies. Of the 49 babies with multiple malformations, 21 [42.8%] had recognized syndromes, most of which were autosomal recessive and 17 had chromosomal aberrations. Isolated systems anomalies included central nervous system [12 cases], cardiovascular system [9 cases], skeletal system [7 cases] and gastrointestinal system [6 cases]. Of the parents, 68% were consanguineous. Genetic factors were implicated in 79% of cases. Genetic services need to be provided as an effective means for the prevention of these disorders

Biotinidase deficiency: a treatable genetic disorder in the Saudi population

Biotinidase deficiency is an autosomal recessive genetic disorder which is not uncommon in the Saudi population. Biotinidase is responsible for biotin recycling and biotin is an essential cofactor for activation of the carboxylase enzymes. Absence of biotinidase leads to infantile or early childhood encephalopathy, seizure disorder, dermatitis, alopecia, neural deafness and optic atrophy. The disease can be diagnosed by simple fluorometric enzyme assay. Treatment with biotin is both cheap and simple, resulting in rewarding clinical recovery and normalization of the biochemical, neuroradiological and neurophysiological parameters. If neglected, however, a patient may die of acute metabolic acidosis or may suffer from permanent neural deafness and optic atrophy, with mental and motor handicap. We describe the detection and treatment of 20 cases of biotinidase deficiency in our hospital and recommend the introduction of a neonatal screening programme for this disorder

Prenatal diagnosis of Hallopeau-Siemens recessive dystrophic epidermolysis bullosa / 中华皮肤科杂志

Objectives To identify the COL7A1 gene mutation in a recessive dystrophic epidermolysis bullosa (RDEB) family, and to perform prenatal diagnosis in the patient's offspring. Methods The genomic DNA, obtained from the patient and his wife, was used to screen all 118 exons of the type VII collagen gene (COL7A1) via polymerase chain reaction (PCR) followed by direct DNA sequencing of the PCR products. Fetal DNA was extracted from amniotic fluid of the patient's wife at the 15th week of gestation. PCR, direct DNA sequencing and restriction fragment length polymorphisms (RFLPs) were performed for prenatal diagnosis. Results The patient in this study was a compound heterozygote for a S48P missense mutation in exon 2 and an 11 base pair deletion (3625del11) leading to a premature termination codon (PTC) in exon 27, which are a novel combination of COL7A1 mutations in RDEB. The COL7A1 genotype of his wife was normal. In the fetus, the same deletion of 11 base pair (3625del11) was found in exon 27, but no mutation was found in exon 2. Thus, the fetus was predicted to be a clinically normal child with a carrier genotype. Seven months later, a clinically unaffected male infant was born and the prediction was confirmed. Conclusion We successfully performed the first DNA-based prenatal diagnosis in China in a family with Hallopeau-Siemens RDEB.