Whole exome sequencing identifies the first STRADA point mutation in a patient with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE).

Am J Med Genet A. 2016 Aug;170(8):2181-5

Authors: Bi W, Glass IA, Muzny DM, Gibbs RA, Eng CM, Yang Y, Sun A

Abstract
Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is an ultra rare neurodevelopmental disorder characterized by severe, infantile-onset intractable epilepsy, neurocognitive delay, macrocephaly, and craniofacial dysmorphism. The molecular diagnosis of this condition has thus far only been made in 16 Old Order Mennonite patients carrying a homozygous 7 kb founder deletion of exons 9-13 of STRADA. We performed clinical whole exome sequencing (WES) on a 4-year-old Indian male with global developmental delay, history of failure to thrive, infantile spasms, repetitive behaviors, hypotonia, low muscle mass, marked joint laxity, and dysmorphic facial features including tall forehead, long face, arched eyebrows, small chin, wide mouth, and tented upper lip. A homozygous single nucleotide duplication, c.842dupA (p.D281fs), in exon 10 of STRADA was identified. Sanger sequencing confirmed the mutation in the individual and identified both parents as carriers. In light of the molecular discoveries, the patient's clinical phenotype was considered to be a good fit for PMSE. We identified for the first time a homozygous point mutation in STRADA causing PMSE. Additional bi-allelic mutations related to PMSE thus far have not been observed in Baylor ∼6,000 consecutive clinical WES cases, supporting the rarity of this disorder. Our findings may have treatment implications for the patient since previous studies have shown rapamycin as a potential therapeutic agent for the seizures and cognitive problems in PMSE patients. © 2016 Wiley Periodicals, Inc.

PMID: 27170158 [PubMed - indexed for MEDLINE]

How many cases of disease in a pedigree imply familial disease?

Ann Hum Genet. 2017 Oct 23;:

Authors: Dudbridge F, Brown SJ, Ward L, Wilson SG, Walsh JP

Abstract
The ability to perform whole-exome and, increasingly, whole-genome sequencing on large numbers of individuals has led to increased efforts to identify rare genetic variants that affect the risk of both common and rare diseases. In such applications, it is important to identify families that are segregating the rare variants of interest. For rare diseases or rare familial forms of common diseases, pedigrees with multiple affected members are clearly harbouring risk variants. For more common diseases, however, it may be unclear whether a family with a few affected members is segregating a familial disease, is the result of multiple sporadic cases, or is a mixture of familial cases and phenocopies. We provide calculations for the probability that a family is harbouring familial disease, presented in general terms that admit working guidelines for selecting families for current sequencing studies. Using examples motivated by our own studies of thyroid cancer and published studies of colorectal cancer, we show that for common diseases, families with exactly two affected first-degree relatives have only a moderate probability of segregating familial disease, but this probability is higher for families with three or more affected relatives, and those families should therefore be prioritised in sequencing studies.

PMID: 29058319 [PubMed - as supplied by publisher]

Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome.

Pediatr Nephrol. 2017 Oct 23;:

Authors: Dorval G, Gribouval O, Martinez-Barquero V, Machuca E, Tête MJ, Baudouin V, Benoit S, Chabchoub I, Champion G, Chauveau D, Chehade H, Chouchane C, Cloarec S, Cochat P, Dahan K, Dantal J, Delmas Y, Deschênes G, Dolhem P, Durand D, Ekinci Z, El Karoui K, Fischbach M, Grunfeld JP, Guigonis V, Hachicha M, Hogan J, Hourmant M, Hummel A, Kamar N, Krummel T, Lacombe D, Llanas B, Mesnard L, Mohsin N, Niaudet P, Nivet H, Parvex P, Pietrement C, de Pontual L, Noble CP, Ribes D, Ronco P, Rondeau E, Sallee M, Tsimaratos M, Ulinski T, Salomon R, Antignac C, Boyer O

Abstract
BACKGROUND: Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease.
METHODS: Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort.
RESULTS: Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing.
CONCLUSIONS: Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.

PMID: 29058154 [PubMed - as supplied by publisher]

Early-Onset LMNA-Associated Muscular Dystrophy with Later Involvement of Contracture.

J Clin Neurol. 2017 Oct;13(4):405-410

Authors: Lee Y, Lee JH, Park HJ, Choi YC

Abstract
BACKGROUND AND PURPOSE: The early diagnosis of LMNA-associated muscular dystrophy is important for preventing sudden arrest related to cardiac conduction block. However, diagnosing early-onset Emery-Dreifuss muscular dystrophy (EDMD) with later involvement of contracture and limb-girdle muscular dystrophy type 1B is often delayed due to heterogeneous clinical presentations. We aimed to determine the clinical features that contribute to a delayed diagnosis.
METHODS: We reviewed four patients who were recently diagnosed with LMNA-associated muscular dystrophy by targeted exome sequencing and who were initially diagnosed with nonspecific or other types of muscular dystrophy.
RESULTS: Certain clinical features such as delayed contracture involvement and calf hypertrophy were found to contribute to a delayed diagnosis. Muscle biopsies were not informative for the diagnosis in these patients.
CONCLUSIONS: Genetic testing of single or multiple genes is useful for confirming a diagnosis of LMNA-associated muscular dystrophy. Even EDMD patients could experience the later involvement of contracture, so clinicians should consider early genetic testing for patients with undiagnosed muscular dystrophy or laminopathy.

PMID: 29057633 [PubMed]

Homozygous mutations in PJVK and MYO15A genes associated with non-syndromic hearing loss in Moroccan families.

Int J Pediatr Otorhinolaryngol. 2017 Oct;101:25-29

Authors: Salime S, Charif M, Bousfiha A, Elrharchi S, Bakhchane A, Charoute H, Kabine M, Snoussi K, Lenaers G, Barakat A

Abstract
OBJECTIVES: Autosomal recessive non-syndromic hearing loss is a heterogeneous disorder and the most prevalent human genetic sensorineural defect. In this study, we investigated the geneticcause of sensorineural hearing loss in Moroccan patients and presented the importance of whole exome sequencing (WES) to identify candidate genes in two Moroccan families with profound deafness.
METHODS: After excluding mutations previously reported in Moroccan deaf patients, whole exome sequencing was performed and Sanger sequencing was used to validate mutations in these genes.
RESULTS: Our results disclosed the c.113_114insT (p.Lys41GlufsX8) and c.406C > T (p.Arg130X) homozygous mutations in PJVK and a homozygous c.5203C > T (p.Arg1735Trp) mutation in MYO15A, both genes responsible for non-syndromic recessive hearing loss DFNB59 and DFNB3, respectively.
CONCLUSION: We identified in Moroccan deaf patients two mutations in PJVK and one mutation in MYO15A described for the first time in association with non-syndromic recessive hearing loss. These results emphasize that whole exome sequencing is a powerful diagnostic strategy to identify pathogenic mutations in heterogeneous disorders with many various causative genes.

PMID: 28964305 [PubMed - indexed for MEDLINE]

Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and Is Associated With Worse Outcome in Adenoid Cystic Carcinoma.

Am J Surg Pathol. 2017 Nov;41(11):1473-1482

Authors: Sajed DP, Faquin WC, Carey C, Severson EA, H Afrogheh A, A Johnson C, Blacklow SC, Chau NG, Lin DT, Krane JF, Jo VY, Garcia JJ, Sholl LM, Aster JC

Abstract
NOTCH1 is frequently mutated in adenoid cystic carcinoma (ACC). To test the idea that immunohistochemical (IHC) staining can identify ACCs with NOTCH1 mutations, we performed IHC for activated NOTCH1 (NICD1) in 197 cases diagnosed as ACC from 173 patients. NICD1 staining was positive in 194 cases (98%) in 2 major patterns: subset positivity, which correlated with tubular/cribriform histology; and diffuse positivity, which correlated with a solid histology. To determine the relationship between NICD1 staining and NOTCH1 mutational status, targeted exome sequencing data were obtained on 14 diffusely NICD1-positive ACC specimens from 11 patients and 15 subset NICD1-positive ACC specimens from 15 patients. This revealed NOTCH1 gain-of-function mutations in 11 of 14 diffusely NICD1-positive ACC specimens, whereas all subset-positive tumors had wild-type NOTCH1 alleles. Notably, tumors with diffuse NICD1 positivity were associated with significantly worse outcomes (P=0.003). To determine whether NOTCH1 activation is unique among tumors included in the differential diagnosis with ACC, we performed NICD1 IHC on a cohort of diverse salivary gland and head and neck tumors. High fractions of each of these tumor types were positive for NICD1 in a subset of cells, particularly in basaloid squamous cell carcinomas; however, sequencing of basaloid squamous cell carcinomas failed to identify NOTCH1 mutations. These findings indicate that diffuse NICD1 positivity in ACC correlates with solid growth pattern, the presence of NOTCH1 gain-of-function mutations, and unfavorable outcome, and suggest that staining for NICD1 can be helpful in distinguishing ACC with solid growth patterns from other salivary gland and head and neck tumors.

PMID: 28914715 [PubMed - indexed for MEDLINE]

GNPAT rs11558492 is not a Major Modifier of Iron Status: Study of Italian Hemochromatosis Patients and Blood Donors.

Ann Hepatol. 2017 May - Jun;16(3):451-456

Authors: Greni F, Valenti L, Mariani R, Pelloni I, Rametta R, Busti F, Ravasi G, Girelli D, Fargion S, Galimberti S, Piperno A, Pelucchi S

Abstract
BACKGROUND AND AIM: HFE-related Hemochromatosis (HH) is characterized by marked phenotype heterogeneity, probably due to the combined action of acquired and genetic factors. Among them, GNPAT rs11558492 was proposed as genetic modifier of iron status, but results are still controversial. To shed light on these discrepancies, we genotyped 298 Italian p.C282Y homozygotes and 169 healthy controls.
MATERIAL AND METHODS: Allele and genotype frequencies were analysed and compared with those reported in Exome Variant Server (EVS). To explore the role of rs11558492 as a potential modifier of iron status, serum ferritin (SF), liver iron concentration (LIC) and iron removed (IR) were studied according to allele and genotype frequencies. In addition, the effect of the SNP on liver fibrosis was examined comparing patients with absent/mild-moderate fibrosis to those with severe fibrosis-cirrhosis.
RESULTS: GNPAT rs11558492 minor allele (G) frequency (MAF) was 20.3% in HFE-HH, 17.2% in controls and 20.6% in EVS database. Genotype frequencies were 64% and 69.2% (AA), 31.2% and 27.2% (AG), 4.8% and 3.6% (GG) in HFE-HH and controls, respectively. No significant differences were found comparing genotype and allele frequencies even selecting subgroups of only-males with extreme phenotypes and low alcohol intake. SF, IR and LIC levels did not significantly differ according to rs11558492 genotypes. Also, MAF did not differ between patients with absent/mild fibrosis and severe fibrosis/cirrhosis.
CONCLUSIONS: Our findings indicate that GNPAT rs11558492 is not a major modifier of iron status and is not associated with liver fibrosis in HFE-HH patients.

PMID: 28425416 [PubMed - indexed for MEDLINE]

A splice site mutation in HERC1 leads to syndromic intellectual disability with macrocephaly and facial dysmorphism: Further delineation of the phenotypic spectrum.

Am J Med Genet A. 2016 Jul;170(7):1868-73

Authors: Aggarwal S, Bhowmik AD, Ramprasad VL, Murugan S, Dalal A

Abstract
We report on a sib pair of Indian origin presenting with intellectual disability, dysmorphism, and macrocephaly. Exome sequencing revealed a homozygous splice site HERC1 mutation in both probands. Functional analysis revealed use of an alternate splice site resulting in formation of a downstream stop codon and nonsense mediated decay. In the light of recent reports of HERC1 mutations in two families with a similar phenotypic presentation, this report reiterates the pathogenic nature and clinical consequences of HERC1 disruption. © 2016 Wiley Periodicals, Inc.

PMID: 27108999 [PubMed - indexed for MEDLINE]

Confirmation of TENM3 involvement in autosomal recessive colobomatous microphthalmia.

Am J Med Genet A. 2016 Jul;170(7):1895-8

Authors: Chassaing N, Ragge N, Plaisancié J, Patat O, Geneviève D, Rivier F, Malrieu-Eliaou C, Hamel C, Kaplan J, Calvas P

Abstract
Anophthalmia and microphthalmia are the most severe malformations of the eye, referring to a congenital absence, and a reduced size of the eyeball respectively. More than 20 genes have been shown to be mutated in patients with syndromic and non-syndromic forms of anophthalmia-microphthalmia. In a recent study combining autozygome and exome analysis, a homozygous loss of function mutation in TENM3 (previously named ODZ3) was reported in two siblings with isolated bilateral colobomatous microphthalmia from a consanguineous Saudi family. Herein, we report a third patient (not related to the previously reported family) with bilateral colobomatous microphthalmia and developmental delay in whom genetic studies identified a homozygous TENM3 splicing mutation c.2968-2A>T (p.Val990Cysfs*13). This report supports the association of TENM3 mutations with colobomatous microphthalmia and expands the phenotypic spectrum associated with mutations in this gene. © 2016 Wiley Periodicals, Inc.

PMID: 27103084 [PubMed - indexed for MEDLINE]

Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia.

Brain. 2017 Oct 06;:

Authors: Nibbeling EAR, Duarri A, Verschuuren-Bemelmans CC, Fokkens MR, Karjalainen JM, Smeets CJLM, de Boer-Bergsma JJ, van der Vries G, Dooijes D, Bampi GB, van Diemen C, Brunt E, Ippel E, Kremer B, Vlak M, Adir N, Wijmenga C, Warrenburg BPCV, Franke L, Sinke RJ, Verbeek DS

Abstract
The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types.

PMID: 29053796 [PubMed - as supplied by publisher]

De novo mutations of TUBA3D are associated with keratoconus.

Sci Rep. 2017 Oct 19;7(1):13570

Authors: Hao XD, Chen P, Zhang YY, Li SX, Shi WY, Gao H

Abstract
Keratoconus (KC) is a common degenerative corneal disease, and heredity plays a key role in its development. Although few genes are known to cause KC, a large proportion of disease-causing genes remain to be revealed. Here, we report the identification of TUBA3D as a novel gene linked to KC. Using whole-exome sequencing of a twins pedigree, a novel de novo mutation (c.31 C > T, p.Gln11stop) in TUBA3D gene was identified. A screening performed in 200 additional unrelated patients with KC revealed another two mutations (c.201insTT, p.Val68Leufs*2; c.*2 G > A) in two patients. TUBA3D was expressed highly in the cornea, and the twins had lower TUBA3D expression and higher UPA and MMP1 expressions than the normal parents. Through function prediction and in vitro cell experiment, we further demonstrated that the mutant proteins of TUBA3D were unstable and could lead to human corneal fibroblast cells performing higher MMPs expression and oxidative stress. These changes thus reduce the amount of extracellular matrices within corneas and undoubtedly play a major role in stromal thinning, which is characteristic of KC corneas. Our study showed that TUBA3D is a new gene that causes KC, thus supporting the evidence that this protein has an additional function into the human cornea.

PMID: 29051577 [PubMed - in process]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

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13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2017/10/20

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A novel inborn error of the Coenzyme Q10 biosynthesis pathway: Cerebellar ataxia and static encephalomyopathy due to COQ5 C-Methyltransferase deficiency.

Hum Mutat. 2017 Oct 16;:

Authors: Malicdan MCV, Vilboux T, Ben-Zeev B, Guo J, Eliyahu A, Pode-Shakked B, Dori A, Kakani S, Chandrasekharappa SC, Ferreira C, Shelestovich N, Marek-Yagel D, Pri-Chen H, Blatt I, Niederhuber JE, He L, Toro C, Taylor RW, Deeken J, Yardeni T, Wallace DC, Gahl WA, Anikster Y

Abstract
Primary coenzyme Q10 (CoQ10 ; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ10 , and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ10 synthetic pathway, have not been implicated in human disease. Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures and cognitive disability. Whole exome and subsequent whole genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement and increased the concentrations of CoQ10 in blood. This is the first report of primary CoQ10 deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological and molecular features, and insights regarding targeted treatment with CoQ10 supplementation. This article is protected by copyright. All rights reserved.

PMID: 29044765 [PubMed - as supplied by publisher]

Exome Sequencing Identifies a Novel Nonsense Mutation of MYO6 as the Cause of Deafness in a Brazilian Family.

Ann Hum Genet. 2017 Oct 17;:

Authors: Sampaio-Silva J, Batissoco AC, Jesus-Santos R, Abath-Neto O, Scarpelli LC, Nishimura PY, Galindo LT, Bento RF, Oiticica J, Lezirovitz K

Abstract
We investigated 313 unrelated subjects who presented with hearing loss to identify the novel genetic causes of this condition in Brazil. Causative GJB2/GJB6 mutations were found in 12.7% of the patients. Among the familial cases (100/313), four were selected for exome sequencing. In one case, two novel heterozygous variants were found and were predicted to be pathogenic based on bioinformatics tools, that is, p.Ser906* (MYO6) and p.Arg42Cys (GJB3). We confirmed that this nonsense MYO6 mutation segregated with deafness in this family. Only the proband and her unaffected mother exhibited the GJB3 mutation, which is in the same amino acid of a known Erythrokeratodermia variabilis mutation. None of the patients exhibited this skin disease, but the proband exhibited a more severe hearing loss. Hence, the GJB3 mutation was considered to be a variant of uncertain significance. In conclusion, we described a novel nonsense MYO6 mutation that was responsible for the hearing loss in a Brazilian family. This mutation resides in the neck domain of myosin-VI after the motor domain. Thus, our data give further support for genotype-phenotype correlations, which state that when the motor domain of the protein is functioning, the hearing loss is milder and has a later onset. The three remaining families without mutations in the known genes suggest that there are still deafness genes to be revealed.

PMID: 29044474 [PubMed - as supplied by publisher]

Evaluating phenotype-driven approaches for genetic diagnoses from exomes in a clinical setting.

Sci Rep. 2017 Oct 18;7(1):13509

Authors: Pengelly RJ, Alom T, Zhang Z, Hunt D, Ennis S, Collins A

Abstract
Next generation sequencing is transforming clinical medicine and genome research, providing a powerful route to establishing molecular diagnoses for genetic conditions; however, challenges remain given the volume and complexity of genetic variation. A number of methods integrate patient phenotype and genotypic data to prioritise variants as potentially causal. Some methods have a clinical focus while others are more research-oriented. With clinical applications in mind we compare results from alternative methods using 21 exomes for which the disease causal variant has been previously established through traditional clinical evaluation. In this case series we find that the PhenIX program is the most effective, ranking the true causal variant at between 1 and 10 in 85% of these cases. This is a significantly higher proportion than the combined results from five alternative methods tested (p = 0.003). The next best method is Exomiser (hiPHIVE), in which the causal variant is ranked 1-10 in 25% of cases. The widely different targets of these methods (more clinical focus, considering known Mendelian genes, in PhenIX, versus gene discovery in Exomiser) is perhaps not fully appreciated but may impact strongly on their utility for molecular diagnosis using clinical exome data.

PMID: 29044180 [PubMed - in process]

Focal segmental glomerulosclerosis associated with mitochondrial disease.

Clin Nephrol Case Stud. 2017;5:20-25

Authors: Lim K, Steele D, Fenves A, Thadhani R, Heher E, Karaa A

Abstract
Primary mitochondrial diseases (MD) are complex, heterogeneous inherited diseases caused by mutations in either the mitochondrial or nuclear DNA. Glomerular diseases in MD have been reported with tRNA mutation m.3243A>G causing a syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). We describe here a case of focal segmental glomerulosclerosis (FSGS) associated with a new tRNA mutation site. A 34-year-old man with a history of living related kidney transplantation, diabetes, hearing loss, and developmental delay presented to the outpatient clinic with complaints of new behavioral difficulties, worsening symptoms, and brain involvement on imaging. Physical examination was remarkable for difficulty hearing, a pattern of dysarthric speech, and cerebellar gait. Laboratory investigations including lactate levels were unremarkable. Based on this set of clinical circumstances, concern for an underlying genetic abnormality was raised. Multiple metabolic tests were unremarkable. Whole exome sequencing revealed a mitochondrial MT-TW tRNA change at position m.5538G>A. Genotype-phenotype correlations are consistent with this tRNA mutation as a cause of his symptoms. To the best of our knowledge, this is the first case describing FSGS-associated MD caused by an m.5538 G>A mutation. Consideration of an underlying MD should be made in patients presenting with deafness, neurologic changes, diabetes, and renal failure.

PMID: 29043143 [PubMed]

Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy.

Hum Mol Genet. 2017 Oct 05;:

Authors: Peng Y, Shinde DN, Valencia AC, Mo JS, Rosenfeld J, Truitt Cho M, Chamberlin A, Li Z, Liu J, Gui B, Brockhage R, Basinger A, Alvarez-Leon B, Heydemann P, Magoulas PL, Lewis AM, Scaglia F, Gril S, Chong SC, Bower M, Monaghan KG, Willaert R, Plona MR, Dineen R, Milan F, Hoganson G, Powis Z, Helbig KL, Keller-Ramey J, Harris B, Anderson LC, Green T, Sukoff Rizzo SJ, Kaylor J, Chen J, Guan MX, Sellars E, Sparagana SP, Gibson JB, Reinholdt LG, Tang S, Huang T

Abstract
Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.

PMID: 29040572 [PubMed - as supplied by publisher]

[Neuroacanthocytosis diagnosis with new generation whole exome sequencing].

Orv Hetil. 2017 Oct;158(42):1681-1684

Authors: Hadzsiev K, Szőts M, Fekete A, Balikó L, Boycott K, Nagy F, Melegh B

Abstract
In a patient with marked symptoms of Huntington disease after the huntingtin testing, which gave normal result, a whole exome sequencing (WES) has been performed based on an international collaboration. A homozygous G>A nucleotid change in the exon 34 of the VPS13A gene has been detected with WES, a mutation resulting in a premature stop codon at the position 1301. This change is a known pathogenic mutation. The aim of this article is to draw attention on the importance of the WES in the diagnosis of rare neurological diseases without any specific symptoms. Orv Hetil. 2017; 158(42): 1681-1684.

PMID: 29037056 [PubMed - in process]

Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice.

PLoS One. 2017;12(9):e0184455

Authors: Chang HH, Moro A, Takakura K, Su HY, Mo A, Nakanishi M, Waldron RT, French SW, Dawson DW, Hines OJ, Li G, Go VLW, Sinnett-Smith J, Pandol SJ, Lugea A, Gukovskaya AS, Duff MO, Rosenberg DW, Rozengurt E, Eibl G

Abstract
Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.

PMID: 28886117 [PubMed - indexed for MEDLINE]