scholarly journals Case Report: Identification of a Novel Homozygous Mutation in GPD1 Gene of a Chinese Child With Transient Infantile Hypertriglyceridemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Haihua Lin ◽  
Youhong Fang ◽  
Lin Han ◽  
Jie Chen ◽  
Jingan Lou ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Underlying Mechanism ◽  
Causative Factor ◽  
Homozygous Mutation ◽  
Clinical Presentations ◽  
Chinese Girl ◽  
Gpd1 Gene ◽  
Generation Sequencing

Transient infantile hypertriglyceridemia is a rare autosomal recessive disorder characterized by hypertriglyceridemia, hypohepatia, hepatomegaly, hepatic steatosis and fibrosis in infancy. Mutations in GPD1 gene are considered the causative factor but the underlying mechanism of this disorder is still enigmatic. To date, only 24 different GPD1 mutations have been reported in the literature worldwide with transient infantile hypertriglyceridemia or relevant conditions. Here we report a Chinese girl who developed hepatomegaly hepatic steatosis, elevated transaminase and hypertriglyceridemia from the age of 4 months. A novel homozygous variant c.454C>T (p.Q152*) was found in GPD1 gene by next-generation sequencing. This patient is the 3rd Asian reported with transient infantile hypertriglyceridemia. We summarized the clinical presentations of transient infantile hypertriglyceridemia and also expanded the spectrum of disease-causing mutations in GPD1.

The utility of reverse phenotyping: a case of lysinuric protein intolerance presented with childhood osteoporosis

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Enise Avci Durmusalioglu ◽  
Esra Isik ◽  
Durdugul Ayyildiz Emecen ◽  
Damla Goksen ◽  
Samim Ozen ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Diagnostic Process ◽  
Homozygous Mutation ◽  
Lysinuric Protein Intolerance ◽  
Case Presentation ◽  
Lysinuric Protein ◽  
Next Generation Sequencing Ngs ◽  
Protein Intolerance ◽  
Generation Sequencing

Abstract Objectives Childhood osteoporosis is often a consequence of a chronic disease or its treatment. Lysinuric protein intolerance (LPI), a rare secondary cause of the osteoporosis, is an autosomal recessive disorder with clinical features ranging from minimal protein intolerance to severe multisystemic involvement. We report a case diagnosed to have LPI using a Next Generation Sequencing (NGS) panel and evaluate the utility of reverse phenotyping. Case presentation A fifteen-year-old-boy with an initial diagnosis of osteogenesis imperfecta, was referred due to a number of atypical findings accompanying to osteoporosis such as splenomegaly and bicytopenia. A NGS panel (TruSight One Sequencing Panel) was performed and a novel homozygous mutation of c.257G>A (p.Gly86Glu) in the SLC7A7 gene (NM_001126106.2), responsible for LPI, was detected. The diagnosis was confirmed via reverse phenotyping. Conclusions Reverse phenotyping using a multigene panel shortens the diagnostic process.

A Case of Congenital Glucose Galactose Malabsorption with a New Mutation in the SLC5A1 Gene

2020 ◽  
Author(s):  
Hasan Akduman ◽  
Dilek Dilli ◽  
Serdar Ceylaner
Keyword(s):  
Mutation Analysis ◽  
Autosomal Recessive ◽  
Glucose Transporter ◽  
Neonatal Period ◽  
Autosomal Recessive Disorder ◽  
Homozygous Mutation ◽  
New Mutation ◽  
Early Neonatal Period ◽  
Sodium Dependent ◽  
Hypernatremic Dehydration

AbstractCongenital glucose-galactose malabsorption (CGGM) is an autosomal recessive disorder originating from an abnormal transporter mechanism in the intestines. It was sourced from a mutation in the SLC5A1 gene, which encodes a sodium-dependent glucose transporter. Here we report a 2-day-old girl with CGGM who presented with severe hypernatremic dehydration due to diarrhea beginning in the first hours of life. Mutation analysis revealed a novel homozygous mutation NM_000343.3 c.127G > A (p.Gly43Arg) in the SLC5A1 gene. Since CGGM can cause fatal diarrhea in the early neonatal period, timely diagnosis of the disease seems to be essential.

Neuropathological Alzheimer’s Disease Lesions in Nasu-Hakola Disease with TREM2 Mutation: Atypical Distribution of Neurofibrillary Changes

2021 ◽  
Vol 79 (1) ◽  
pp. 25-30
Author(s):  
Emanuela Maderna ◽  
Silvia Visonà ◽  
Vittorio Bolcato ◽  
Veronica Redaelli ◽  
Paola Caroppo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Autosomal Recessive ◽  
Cerebral Atrophy ◽  
Autosomal Recessive Disorder ◽  
Homozygous Mutation ◽  
Neurofibrillary Changes ◽  
Axonal Spheroids ◽  
Temporal Structures ◽  
Cortical Involvement

Nasu-Hakola disease is a rare autosomal recessive disorder associated to mutations in TREM2 and DAP12 genes, neuropathologically characterized by leukoencephalopathy with axonal spheroids. We report the neuropathologic findings of a 51-year-old female with a homozygous mutation (Q33X) of TREM2 gene. Beside severe cerebral atrophy and hallmarks of Nasu-Hakola disease, significant Alzheimer’s disease lesions were present. Neurofibrillary changes showed an atypical topographic distribution being severe at spots in the neocortex while sparing the mesial temporal structures. Our finding suggests that TREM2 genetic defects may favor Alzheimer’s disease pathology with neurofibrillary changes not following the hierarchical staging of cortical involvement identified by Braak.

scholarly journals Genetic Analysis of 28 Chinese Families With Tyrosinase-Positive Oculocutaneous Albinism

2021 ◽  
Vol 12 ◽  
Author(s):  
Linya Ma ◽  
Jianjian Zhu ◽  
Jing Wang ◽  
Yazhou Huang ◽  
Jibo Zhang ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Oculocutaneous Albinism ◽  
Type Ii ◽  
Related Disorder ◽  
Chinese Families ◽  
Missense Variants ◽  
Clinical Presentations ◽  
Splicing Variants ◽  
Novel Variants ◽  
Generation Sequencing

BackgroundTyrosinase-positive oculocutaneous albinism (OCA, type II, OCA2) is an autosomal recessive genetic disease in which the biosynthesis of melanin decreases in the skin, hair, and eyes. OCA2 disease is caused by mutations in OCA2 gene. The gene product plays a role in regulating the pH of melanosomes. Up to now, hundreds of OCA2 mutations have been reported and novel variants are still being discovered.MethodsIn this study, we reviewed the records of OCA2 patients who had conducted albinism genetic testing, and then analyzed the clinical and genetic information of 28 OCA2 patients who had been genetically diagnosed by using Sanger sequencing and next-generation sequencing.ResultsIn this study, we reported 31 variants screened from 28 Chinese OCA2 families, and characterized the detailed molecular and clinical presentations. There were 12 novel variants among all detected variants, including 3 missense variants (p.G393V, p.T482A, and p.R720P), 4 frameshift variants (p.R53Gfs∗49, p.N279Kfs∗17, p.I469Lfs∗4, p.I655Nfs∗12), 2 splicing variants (c.1637-2A > G, c.1951 + 1G > C), 2 stopgain variants (p.L278X, p.W652X) and 1 insertion variants (p.P315LinsT). One potential cluster of missense variants was implicated indicating the important roles of the underlying domains in OCA2 pathogenesis.ConclusionOur results were beneficial for diagnosis and precision clinical management for OCA2-related disorder, and this study expanded the mutation spectrum of oculocutaneous albinism.

scholarly journals Loss of peptide:N-glycanase causes proteasome dysfunction mediated by a sugar-recognizing ubiquitin ligase

2021 ◽  
Vol 118 (27) ◽  
pp. e2102902118
Author(s):  
Yukiko Yoshida ◽  
Makoto Asahina ◽  
Arisa Murakami ◽  
Junko Kawawaki ◽  
Meari Yoshida ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Ubiquitin Ligase ◽  
Autosomal Recessive ◽  
Transcriptional Activity ◽  
Autosomal Recessive Disorder ◽  
Underlying Mechanism ◽  
Transcriptional Factor ◽  
Nuclear Factor ◽  
Substantial Inhibition ◽  
Proteasome Subunits

Mutations in the human peptide:N-glycanase gene (NGLY1), which encodes a cytosolic de–N-glycosylating enzyme, cause a congenital autosomal recessive disorder. In rodents, the loss of Ngly1 results in severe developmental delay or lethality, but the underlying mechanism remains unknown. In this study, we found that deletion of Fbxo6 (also known as Fbs2), which encodes a ubiquitin ligase subunit that recognizes glycoproteins, rescued the lethality-related defects in Ngly1-KO mice. In NGLY1-KO cells, FBS2 overexpression resulted in the substantial inhibition of proteasome activity, causing cytotoxicity. Nuclear factor, erythroid 2–like 1 (NFE2L1, also known as NRF1), an endoplasmic reticulum–associated transcriptional factor involved in expression of proteasome subunits, was also abnormally ubiquitinated by SCFFBS2 in NGLY1-KO cells, resulting in its retention in the cytosol. However, the cytotoxicity caused by FBS2 was restored by the overexpression of “glycan-less” NRF1 mutants, regardless of their transcriptional activity, or by the deletion of NRF1 in NGLY1-KO cells. We conclude that the proteasome dysfunction caused by the accumulation of N-glycoproteins, primarily NRF1, ubiquitinated by SCFFBS2 accounts for the pathogenesis resulting from NGLY1 deficiency.

scholarly journals Cone Dystrophy in Patient with HomozygousRP1L1Mutation

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Sachiko Kikuchi ◽  
Shuhei Kameya ◽  
Kiyoko Gocho ◽  
Said El Shamieh ◽  
Keiichiro Akeo ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Cone Dystrophy ◽  
Homozygous Mutation ◽  
Full Field ◽  
Clinical Evaluations ◽  
Normal Visual Acuity ◽  
Severe Reduction ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Cone Density

The purpose of this study was to determine whether an autosomal recessive cone dystrophy was caused by a homozygousRP1L1mutation. A family including one subject affected with cone dystrophy and four unaffected members without evidence of consanguinity underwent detailed ophthalmic evaluations. The ellipsoid and interdigitation zones on the spectral-domain optical coherence tomography images were disorganized in the proband. The proband had a reduced amplitude of cone and flicker full-field electroretinograms (ERGs). Focal macular ERGs and multifocal ERGs were severely reduced in the proband. A homozygousRP1L1mutation (c.3628T>C, p.S1210P) was identified in the proband. Family members who were heterozygous for the p.S1210P mutation had normal visual acuity and normal results of clinical evaluations. To investigate other putative pathogenic variant(s), a next-generation sequencing (NGS) approach was applied to the proband. NGS identified missense changes in the heterozygous state of thePCDH15,RPGRIP1, andGPR98genes. None of these variants cosegregated with the phenotype and were predicted to be benign reinforcing the putative pathogenicity of theRP1L1homozygous mutation. The AO images showed a severe reduction of the cone density in the proband. Our findings indicate that a homozygous p.S1210P exchange in theRP1L1gene can cause cone dystrophy.

scholarly journals Apparent mineralocorticoid excess syndrome in a Brazilian boy caused by the homozygous missense mutation p.R186C in the HSD11B2 gene

2008 ◽  
Vol 52 (8) ◽  
pp. 1277-1281 ◽  
Author(s):  
Fernanda Borchers Coeli ◽  
Lúcio Fábio Caldas Ferraz ◽  
Sofia H. V. de Lemos-Marini ◽  
Sumara Zuanazi Pinto Rigatto ◽  
Vera Maria Santoro Belangero ◽  
...  
Keyword(s):  
Mineralocorticoid Receptor ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disorder ◽  
Homozygous Mutation ◽  
Molecular Studies ◽  
Apparent Mineralocorticoid Excess ◽  
Gene Maps ◽  
Apparent Mineralocorticoid Excess Syndrome

The apparent mineralocorticoid excess syndrome (AME) is a rare autosomal recessive disorder due to the deficiency of 11β-hydroxysteroid dehydrogenase type 2 enzyme (11beta-HSD2). The 11beta-HSD2 enzyme, encoded by HSD11B2 gene, metabolizes active cortisol in cortisone. Mutations on HSD11B2 gene affect the enzyme activity by leading to an excess of cortisol, which causes its inappropriate access to mineralocorticoid receptor. Therefore, cortisol will bind mineralocorticoid receptor. The human HSD11B2 gene maps to chromosome 16q22 and consists of five exons encoding a protein of 405 amino acids. We present here clinical and molecular studies on a Brazilian boy who was born pre-term after an oligodramnious pregnancy. He was diagnosed as having AME at the age of 26 months. His parents are second cousins. Molecular characterization of the HSD11B2 gene revealed the homozygous mutation p.R186C. The patient described here is the second case of HDS11B2 gene mutation reported in Brazilian patients with AME.

scholarly journals Five Novel Mutations in LOXHD1 Gene Were Identified to Cause Autosomal Recessive Nonsyndromic Hearing Loss in Four Chinese Families

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Xiaohui Bai ◽  
Chi Zhang ◽  
Fengguo Zhang ◽  
Yun Xiao ◽  
Yu Jin ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
Corneal Dystrophy ◽  
Underlying Mechanism ◽  
Nonsyndromic Hearing Loss ◽  
Novel Mutations ◽  
Chinese Families ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing ◽  
Autosomal Recessive Pattern

Hearing loss is one of the most common sensory disorders in newborns and is mostly caused by genetic factors. Autosomal recessive nonsyndromic hearing loss (ARNSHL) is usually characterized as a severe-to-profound congenital sensorineural hearing loss and later can cause various degrees of defect in the language and intelligent development of newborns. The mutations in LOXHD1 gene have been shown to cause DFNB77, a type of ARNSHL. To date, there are limited reports about the association between LOXHD1 gene and ARNSHL. In this study, we reported six patients from four Chinese families suffering from severe-to-profound nonsyndromic hearing loss. We performed targeted next generation sequencing in the six affected members and identified five novel pathogenic mutations in LOXHD1 including c.277G>A (p.D93N), c.611-2A>T, c.1255+3A>G, c.2329C>T (p.Q777∗), and c.5888delG (p.G1963Afs∗136). These mutations were confirmed to be cosegregated with the hearing impairment in the families by Sanger sequencing and were inherited in an autosomal recessive pattern. All of the five mutations were absent in 200 control subjects. There were no symptoms of Fuchs corneal dystrophy in the probands and their blood-related relatives. We concluded that these five novel mutations could be involved in the underlying mechanism resulting in the hearing loss, and this discovery expands the genotypic spectrum of LOXHD1 mutations.

scholarly journals Mitochondrial Neurogastrointestinal Encephalomyopathy Disease in Three Siblings from Pakistan with a Novel Mutation

2018 ◽  
Vol 08 (01) ◽  
pp. 015-019
Author(s):  
Sana Durrani ◽  
Bee Chen ◽  
Yusnita Yakob ◽  
Lua Hian ◽  
Bushra Afroze
Keyword(s):  
Thymidine Phosphorylase ◽  
Autosomal Recessive ◽  
Novel Mutation ◽  
Gastrointestinal Symptoms ◽  
Autosomal Recessive Disorder ◽  
Homozygous Mutation ◽  
Pakistani Family ◽  
Mitochondrial Neurogastrointestinal Encephalomyopathy ◽  
Intestinal Dysmotility ◽  
Sensorineural Hearing Impairment

AbstractMitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystem autosomal recessive disorder. The disease is clinically heterogeneous with gastrointestinal symptoms of intestinal dysmotility and cachexia as well as neurological symptoms of ophthalmoplegia, neuropathy, sensorineural hearing impairment, and diffuse leukoencephalopathy being most prominent. MNGIE is caused by mutations in TYMP, a gene that encodes thymidine phosphorylase (TP)—a cytosolic enzyme. Mutations in TYMP lead to very low TP catalytic activity, resulting in dramatically increased thymidine and deoxyuridine in plasma. We describe the clinical, biochemical, and neuroimaging findings of three boys with MNGIE from a Pakistani family with a novel homozygous mutation, c.798_801dupCGCG p. (Ala268Argfs*?), in exon 7 of TYMP.

scholarly journals Prenatal Identification of a Novel Mutation in the MCPH1 Gene Associated with Autosomal Recessive Primary Microcephaly (MCPH) using Next Generation Sequencing (NGS)

2021 ◽  
Author(s):  
Ioannis Papoulidis ◽  
Makarios Eleftheriades ◽  
Emmanouil Manolakos ◽  
Simoni Maria Liapi ◽  
Anastasia Konstantinidou ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Tandem Repeats ◽  
Novel Mutation ◽  
Homozygous Mutation ◽  
Primary Microcephaly ◽  
Strong Connection ◽  
C Terminus ◽  
Next Generation Sequencing Ngs ◽  
Autosomal Recessive Primary Microcephaly ◽  
Generation Sequencing

MCPH1, otherwise known as the microcephalin gene (*607117) and protein, is a basic regulator of chromosome condensation (BCRT-BRCA1 C-terminus). The Microcephalin protein is made up of three BCRT domains and conserved tandem repeats of interacting phospho-peptide. There is a strong connection between mutations of the MCPH1 and reduced brain growth. Specifically, individuals with such mutations have underdeveloped brains which means smaller size, varying levels of mental retardation, delayed speech and poor language skills, individuals with mild microcephaly and normal intelligence notwithstanding. In this case, a fetus with novel homozygous mutation of the MCPH1 gene ((c.348del)), whose parents were recessive heterozygous for (c.348del), displayed severe microcephaly at 22 weeks of gestation. Due to the effect on splice sites in introns, this mutation causes forming of dysfunctional proteins which lack crucial domains of the C-terminus. Our findings portray an association between the new MCPH1 mutation ((c.348del)) and the clinical features of autosomal recessive primary microcephaly (MCPH) contributing to a broader spectrum related to these pathologies.

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