Nuclear Factor κB Activation in a Type V Pityriasis Rubra Pilaris Patient Harboring Multiple CARD14 Variants.

Front Immunol. 2018;9:1564

Authors: Danis J, Göblös A, Gál B, Sulák A, Farkas K, Török D, Varga E, Korom I, Kemény L, Széll M, Bata-Csörgö Z, Nagy N

Abstract
Pityriasis rubra pilaris (PRP) is a rare papulosquamous skin disorder, which is phenotypically related to psoriasis. Some familial PRP cases show autosomal dominant inheritance due to CARD14 mutations leading to increased nuclear factor κB (NFκB) activation. Moreover, CARD14 polymorphisms have also been implicated in sporadic PRP. A Hungarian PRP patient with childhood onset disease showing worsening of the symptoms in adulthood with poor therapeutic response underwent genetic screening for the CARD14 gene, revealing four genetic variants (rs117918077, rs2066964, rs28674001, and rs11652075). To confirm that the identified genetic variants would result in altered NFκB activity in the patient, functional studies were carried out. Immunofluorescent staining of the NFκB p65 subunit and NFκB-luciferase reporter assay demonstrated significantly increased NFκB activity in skin samples and keratinocytes from the PRP patient compared to healthy samples. Characterization of the cytokine profile of the keratinocytes and peripheral blood mononuclear cells demonstrated that the higher NFκB activation in PRP cells induces enhanced responses to inflammatory stimuli. These higher inflammatory reactions could not be explained solely by the observed CARD14 or other inflammation-related gene variants (determined by whole exome sequencing). Thus our study indicates the importance of investigations on other genetic factors related to PRP and their further functional characterization to bring us closer to the understanding of cellular and molecular background of disease pathogenesis.

PMID: 30018619 [PubMed]

Early-onset retinal dystrophy and chronic dermatitis in a girl with an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG).

Ophthalmic Genet. 2018 Jul 18;:1-3

Authors: Khan AO

Abstract
PURPOSE: Early-onset retinal dystrophy is usually isolated but can also be the presenting manifestation of an undiagnosed systemic disease. The purpose of this report is to highlight the initial presentation of a girl with early-onset retinal dystrophy and chronic dermatitis who was found to have an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG).
METHODS: Retrospective case report.
RESULTS: A 13-year-old Baluchi girl was referred for evaluation of low vision since soon after birth. Clinical exam confirmed retinal dystrophy. She also had developmental disability and chronic dermatitis. Brain MRI was normal. Whole exome and confirmatory Sanger sequencing uncovered homozygosity for a SRDA3 deletion (p.Gln96delinsX) that was previously reported in two other Baluchi SRDA3-CDG families with ocular coloboma, optic atrophy, atopic dermatitis, cerebellar hypoplasia, and developmental disability. Early-onset retinal dystrophy was not mentioned in those two families but has since been documented in other SRDA3-CDG families harboring different biallelic variants in the gene.
DISCUSSION: Early-onset retinal dystrophy with chronic dermatitis should raise suspicion for biallelic SRDA3 mutations, particularly in the context of developmental disability. Exome sequencing can be a useful analysis in retinal dystrophy patients with multisystem disease. Homozygosity for the SRDA3 deletion p.Gln96delinsX is not always associated with ocular coloboma.

PMID: 30019980 [PubMed - as supplied by publisher]

Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study.

PLoS Genet. 2018 02;14(2):e1007194

Authors: Eng KH, Szender JB, Etter JL, Kaur J, Poblete S, Huang RY, Zhu Q, Grzesik KA, Battaglia S, Cannioto R, Krolewski JJ, Zsiros E, Frederick PJ, Lele SB, Moysich KB, Odunsi KO

Abstract
Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry. The rate of cancers was 28.4% in paternal grandmother/granddaughter pairs and 13.9% in maternal pairs consistent with an X-linked dominant model (Chi-square test X2 = 0.02, p = 0.89) and inconsistent with an autosomal dominant model (X2 = 20.4, p<0.001). Paternal grandmother cases had an earlier age-of-onset versus maternal cases (hazard ratio HR = 1.59, 95%CI: 1.12-2.25) independent of BRCA1/2 status. Reinforcing the X-linked hypothesis, we observed an association between prostate cancer in men and ovarian cancer in his mother and daughters (odds ratio, OR = 2.34, p = 0.034). Unaffected mothers with affected daughters produced significantly more daughters than sons (ratio = 1.96, p<0.005). We performed exome sequencing in reported BRCA negative cases from the registry. Considering age-of-onset, one missense variant (rs176026 in MAGEC3) reached chromosome-wide significance (Hazard ratio HR = 2.85, 95%CI: 1.75-4.65) advancing the age of onset by 6.7 years. In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An X-linked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. Further work is required to validate this variant and to characterize carrier families.

PMID: 29447163 [PubMed - indexed for MEDLINE]

Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk.

PLoS Genet. 2018 02;14(2):e1007111

Authors: Waller RG, Darlington TM, Wei X, Madsen MJ, Thomas A, Curtin K, Coon H, Rajamanickam V, Musinsky J, Jayabalan D, Atanackovic D, Rajkumar SV, Kumar S, Slager S, Middha M, Galia P, Demangel D, Salama M, Joseph V, McKay J, Offit K, Klein RJ, Lipkin SM, Dumontet C, Vachon CM, Camp NJ

Abstract
The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.

PMID: 29389935 [PubMed - indexed for MEDLINE]

Longitudinal exome-wide association study to identify genetic susceptibility loci for hypertension in a Japanese population.

Exp Mol Med. 2017 Dec 08;49(12):e409;

Authors: Yasukochi Y, Sakuma J, Takeuchi I, Kato K, Oguri M, Fujimaki T, Horibe H, Yamada Y

Abstract
Genome-wide association studies have identified various genetic variants associated with complex disorders. However, these studies have commonly been conducted in a cross-sectional manner. Therefore, we performed a longitudinal exome-wide association study (EWAS) in a Japanese cohort. We aimed to identify genetic variants that confer susceptibility to hypertension using ~244 000 single-nucleotide variants (SNVs) and physiological data from 6026 Japanese individuals who underwent annual health check-ups for several years. After quality control, the association of hypertension with SNVs was tested using a generalized estimating equation model. Finally, our longitudinal EWAS detected seven hypertension-related SNVs that passed strict criteria. Among these variants, six SNVs were densely located at 12q24.1, and an East Asian-specific motif (haplotype) 'CAAAA' comprising five derived alleles was identified. Statistical analyses showed that the prevalence of hypertension in individuals with the East Asian-specific haplotype was significantly lower than that in individuals with the common haplotype 'TGGGT'. Furthermore, individuals with the East Asian haplotype may be less susceptible to the adverse effects of smoking on hypertension. The longitudinal EWAS for the recessive model showed that a novel SNV, rs11917356 of COL6A5, was significantly associated with systolic blood pressure, and the derived allele at the SNV may have spread throughout East Asia in recent evolutionary time.

PMID: 29217820 [PubMed - indexed for MEDLINE]

Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism.

Hum Genomics. 2017 Nov 14;11(1):28

Authors: Alsemari A, Al-Younes B, Goljan E, Jaroudi D, BinHumaid F, Meyer BF, Arold ST, Monies D

Abstract
BACKGROUND: Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency.
RESULTS: A G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic.
CONCLUSIONS: These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.

PMID: 29137650 [PubMed - indexed for MEDLINE]

De novo Mutation in CACNA1S Gene in a 20-Year-Old Man Diagnosed with Metabolic Myopathy.

Arch Iran Med. 2017 Sep;20(9):617-620

Authors: Edizadeh M, Vazehan R, Javadi F, Dehdahsi S, Fadaee M, Faraji Zonooz M, Parsimehr E, Ahangari F, Abolhassani A, Kalhor Z, Fattahi Z, Beheshtian M, Kariminejad A, Akbari MR, Najmabadi H, Nafissi S

Abstract
The calcium channel, voltage-dependent, L-type, alpha 1S subunit (CACNA1S) gene encodes a skeletal Ca2+ channel which is involved in calcium-dependent processes such as muscle contraction and neurotransmitter release. Mutations in this gene have been accompanied by hypo- and normokalemic periodic paralysis, thyrotoxic periodic paralysis, and susceptibility to malignant hyperthermia. We report the clinical and genetic findings in a patient diagnosed with metabolic myopathy who had episodic attacks of muscle pain and weakness but with no family background of the disease. Next-generation sequencing (NGS) using a panel targeting metabolic myopathy and myotonia genes identified a de novo heterozygous pathogenic variant c.3724A>G, p.Arg1242Gly, in exon 30 of CACNA1S. As the second report of this variant, this case may broaden the CACNA1S-related disease spectrum to include normokalemic periodic paralysis.

PMID: 29048924 [PubMed - indexed for MEDLINE]

Multi-genic pattern found in rare type of hypopituitarism: a whole-exome sequencing study of Han Chinese with pituitary stalk interruption syndrome.

J Cell Mol Med. 2017 Dec;21(12):3626-3632

Authors: Guo QH, Wang CZ, Wu ZQ, Qin Y, Han BY, Wang AP, Wang BA, Dou JT, Wu XS, Mu YM

Abstract
Pituitary stalk interruption syndrome (PSIS) is a rare type of hypopituitarism manifesting various degrees of pituitary hormone deficiency. Although mutations have been identified in some familial cases, the underpinning mechanisms of sporadic patients with PSIS who are in a vast majority remain elusive, necessitating a comprehensive study using systemic approaches. We postulate that other genetic mechanisms may be responsible for the sporadic PSIS. To test this hypothesis, we conducted a study in 24 patients with PSIS of Han Chinese with no family history using whole-exome sequencing (WES) and bioinformatic analysis. We identified a group of heterozygous mutations in 92% (22 of 24) of the patients, and these genes are mostly associated with Notch, Shh, Wnt signalling pathways. Importantly, 83% (20 of 24) of the patients had more than one mutation in those pathways suggesting synergy of compound mutations underpin the pathogenesis of sporadic PSIS.

PMID: 28707430 [PubMed - indexed for MEDLINE]

Novel Mutations in EPCAM Cause Congenital Tufting Enteropathy.

J Clin Gastroenterol. 2018 Jan;52(1):e1-e6

Authors: Tang W, Huang T, Xu Z, Huang Y

Abstract
BACKGROUND AND AIMS: Congenital tufting enteropathy (CTE) is a rare autosomal recessive form of intractable diarrhea of infancy. Patients develop chronic diarrhea within days after birth, leading to severe malabsorption and significant mortality. CTE is characterized by subtotal villous atrophy with crypt hyperplasia. Typical features include abnormal villi in the intestinal epithelium and disorganization of surface enterocytes with focal crowding, resembling tufts. The pathogenesis of CTE remains poorly understood. CTE has been reported in Western populations, but until now had not been reported in China. The objective of this study was to identify the gene responsible for CTE in a Chinese individual.
METHODS: A 13-year-old girl with suspected CTE, whose parents were both healthy, was evaluated in our clinic. Tissues were obtained by endoscopy and examined by electron microscopy. Genomic DNA, extracted from the peripheral blood of the child and parents, was subjected to whole-exome sequencing. After mutations in the gene encoding epithelial cell adhesion molecule (EPCAM) were identified, expression of EPCAM was examined by immunohistochemistry staining.
RESULTS: Whole-exome sequencing revealed compound heterozygous mutations in EPCAM in the patient, with immunohistochemical analysis showing complete loss of EPCAM expression in the intestinal villi and crypts.
CONCLUSIONS: We identified compound heterozygous mutations in EPCAM, with loss of EPCAM expression in duodenal enterocytes, in a patient with intractable diarrhea since infancy who was subsequently diagnosed with CTE. This is the first case of CTE to be reported in a Chinese patient.

PMID: 27875355 [PubMed - indexed for MEDLINE]

Biallelic tumor suppressor loss and DNA repair defects in de novo small cell prostate cancer.

J Pathol. 2018 Jul 17;:

Authors: Chedgy EC, Vandekerkhove G, Herberts C, Annala M, Donoghue AJ, Sigouros M, Ritch E, Struss W, Konomura S, Liew J, Parimi S, Vergidis J, Hurtado-Coll A, Sboner A, Fazli L, Beltran H, Chi KN, Wyatt AW

Abstract
Small cell prostatic carcinoma (SCPC) is an aggressive pathology that is managed similarly to small cell lung cancer. SCPC can evolve from prostatic adenocarcinoma in response to androgen deprivation therapy, but in rare cases is present at initial cancer diagnosis. The molecular etiology of de novo SCPC is incompletely understood, due to the scarcity of tumor tissue and the short life expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology and the remainder had some admixed adenocarcinoma foci, but all were treated with first-line platinum-based chemotherapy. Median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin-embedded archival tumor tissue. We observed frequent biallelic deletion and/or mutation of tumor suppressors TP53, RB1 and PTEN, similar to treatment-related SCPC. Indeed, at the RNA level pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes including BRCA1, BRCA2, ATM or MSH2/6, potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harbored ETS gene rearrangements to androgen-driven promoters, consistent with evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape that underlies this unusual pathologic variant, and propose opportunities for targeted therapy strategies in a disease with few treatment options. This article is protected by copyright. All rights reserved.

PMID: 30015382 [PubMed - as supplied by publisher]

Homozygosity for FARSB mutation leads to Phe-tRNA synthetase-related disease of growth restriction, brain calcification, and interstitial lung disease.

Hum Mutat. 2018 Jul 16;:

Authors: Zadjali F, Al-Yahyaee A, Al-Nabhani M, Al-Mubahesi S, Gujjar A, Raniga S, Al-Maawali A

Abstract
Aminoacyl-tRNA synthetases (ARSs) canonical function is to conjugate specific amino acids to cognate tRNA that are required for the first step of protein synthesis. Genetic mutations that cause dysfunction or absence of ARSs result in various neurodevelopmental disorders. The human phenylalanine-tRNA synthetase (PheRS) is a tetrameric protein made of two a subunits coded by FARSA gene and two b subunits coded by FARSB gene. We describe eight affected individuals from an extended family with a multisystemic recessive disease manifest as a significant growth restriction, brain calcifications, and interstitial lung disease. Genome-wide linkage analysis and whole exome sequencing identified homozygosity for a FARSB mutation (NM_005687.4:c.853G > A:p.Glu285Lys) that co-segregate with the disease and likely cause loss-of-function. This study further implicates FARSB mutations in a multisystem, recessive, neurodevelopmental phenotype that share clinical features with the previously known aminoacyl-tRNA synthetase-related diseases. This article is protected by copyright. All rights reserved.

PMID: 30014610 [PubMed - as supplied by publisher]

Whole-Exome Sequencing in Adults With Chronic Kidney Disease.

Ann Intern Med. 2018 Jul 17;169(2):132-133

Authors: Kiryluk K, Groopman E, Rasouly H, Garcia CK, Gharavi AG

PMID: 30014107 [PubMed - in process]

Whole-Exome Sequencing in Adults With Chronic Kidney Disease.

Ann Intern Med. 2018 Jul 17;169(2):131-132

Authors: Chang AR, Luo JZ, Ho K, Mirshahi T, Murray MF

PMID: 30014106 [PubMed - in process]

Multigenic Disease and Bilineal Inheritance in Dilated Cardiomyopathy Is Illustrated in Nonsegregating LMNA Pedigrees.

Circ Genom Precis Med. 2018 Jul;11(7):e002038

Authors: Cowan JR, Kinnamon DD, Morales A, Salyer L, Nickerson DA, Hershberger RE

Abstract
BACKGROUND: We have previously described 19 pedigrees with apparent lamin (LMNA)-related dilated cardiomyopathy (DCM) manifesting in affected family members across multiple generations. In 6 of 19 families, at least 1 individual with idiopathic DCM did not carry the family's LMNA variant. We hypothesized that additional genetic cause may underlie DCM in these families.
METHODS: Affected family members underwent exome sequencing to identify additional genetic cause of DCM in the 6 families with nonsegregating LMNA variants.
RESULTS: In 5 of 6 pedigrees, we identified at least 1 additional rare variant in a known DCM gene that could plausibly contribute to disease in the LMNA variant-negative individuals. Bilineal inheritance was clear or presumed to be present in 3 of 5 families and was possible in the remaining 2. At least 1 individual with a LMNA variant also carried a variant in an additional identified DCM gene in each family. Using a multivariate linear mixed model for quantitative traits, we demonstrated that the presence of these additional variants was associated with a more severe phenotype after adjusting for sex, age, and the presence/absence of the family's nonsegregating LMNA variant.
CONCLUSIONS: Our data support DCM as a genetically heterogeneous disease with, at times, multigene causation. Although the frequency of DCM resulting from multigenic cause is uncertain, our data suggest it may be higher than previously anticipated.

PMID: 30012837 [PubMed - in process]

COL4A3 Gene Variants and Diabetic Kidney Disease in MODY.

Clin J Am Soc Nephrol. 2018 Jul 16;:

Authors: Wang Y, Zhang J, Zhao Y, Wang S, Zhang J, Han Q, Zhang R, Guo R, Li H, Li L, Wang T, Tang X, He C, Teng G, Gu W, Liu F

Abstract
BACKGROUND AND OBJECTIVES: Despite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Whole-exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency <0.05 and predicted to be pathogenic, were selected and analyzed. Immunofluorescence staining of COL4α3 was performed in kidney specimens of patients with DKD with or without R408H and M1209I of COL4A3 variants.
RESULTS: HNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein-protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4α3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY.
CONCLUSIONS: The genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD.

PMID: 30012629 [PubMed - as supplied by publisher]

Genetic Contribution to Risk for Diabetic Kidney Disease.

Clin J Am Soc Nephrol. 2018 Jul 16;:

Authors: Rich SS

PMID: 30012628 [PubMed - as supplied by publisher]

Germline and somatic variations influence the somatic mutational signatures of esophageal squamous cell carcinomas in a Chinese population.

BMC Genomics. 2018 Jul 16;19(1):538

Authors: Guo J, Huang J, Zhou Y, Zhou Y, Yu L, Li H, Hou L, Zhu L, Ge D, Zeng Y, Guleng B, Li Q

Abstract
BACKGROUND: Esophageal squamous cell carcinomas (ESCC) is the fourth most lethal cancer in China. Previous studies reveal several highly conserved mutational processes in ESCC. However, it remains unclear what are the true regulators of the mutational processes.
RESULTS: We analyzed the somatic mutational signatures in 302 paired whole-exome sequencing data of ESCC in a Chinese population for potential regulators of the mutational processes. We identified three conserved subtypes based on the mutational signatures with significantly different clinical outcomes. Our results show that patients of different subpopulations of Chinese differ significantly in the activity of the "NpCpG" signature (FDR = 0.00188). In addition, we report ZNF750 and CDC27, of which the somatic statuses and the genetic burdens consistently influence the activities of specific mutational signatures in ESCC: the somatic ZNF750 status is associated with the AID/APOBEC-related mutational process (FDR = 0.0637); the somatic CDC27 copy-number is associated with the "NpCpG" (FDR = 0.00615) and the AID/APOBEC-related mutational processes (FDR = 8.69 × 10- 4). The burdens of germline variants in the two genes also significantly influence the activities of the same somatic mutational signatures (FDR < 0.1).
CONCLUSIONS: We report multiple factors that influence the mutational processes in ESCC including: the subpopulations of Chinese; the germline and somatic statuses of ZNF750 and CDC27 and exposure to alcohol and tobacco. Our findings based on the evidences from both germline and somatic levels reveal potential genetic regulators of the somatic mutational processes and provide insights into the biology of esophageal carcinogenesis.

PMID: 30012096 [PubMed - in process]

Whole-exome sequencing identifies a novel INS mutation causative of maturity-onset diabetes of the young 10.

J Mol Cell Biol. 2017 Oct 01;9(5):376-383

Authors: Yan J, Jiang F, Zhang R, Xu T, Zhou Z, Ren W, Peng D, Liu Y, Hu C, Jia W

Abstract
Monogenic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygous mutation (p.Ala2Thr) in INS was identified. It was further genotyped in an additional case-control population (6523 cases and 4635 controls), and this variant was observed in 0.09% of cases. Intracellular trafficking of insulin proteins was assessed in INS1-E and HEK293T cells. p.Ala2Thr preproinsulin-GFP was markedly retained in the endoplasmic reticulum (ER) in INS1-E cells. Activation of the PERK-eIF2α-ATF4, IRE1α-XBP1, and ATF6 pathways as well as upregulated ER chaperones were detected in INS1-E cells transfected with the p.Ala2Thr mutant. In conclusion, we identified a causative mutation in INS responsible for maturity-onset diabetes of the young 10 (MODY10) in a Chinese population and demonstrated that this mutation affected β cell function by inducing ER stress.

PMID: 28992123 [PubMed - indexed for MEDLINE]

Clinical subtypes and molecular basis of epidermolysis bullosa in Kuwait.

Int J Dermatol. 2018 Jul 16;:

Authors: Nanda A, Liu L, Al-Ajmi H, Al-Saleh QA, Al-Fadhli S, Anim JT, Ozoemena L, Mellerio JE, McGrath JA

Abstract
BACKGROUND: Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous blistering skin disease, but in countries such as Kuwait, there are very limited data on the clinical and molecular pathology of EB. To improve understanding of EB in Kuwait, we report the experience of a local tertiary referral center over a 17.5 year period (January 2000-June 2017) in establishing clinical and molecular diagnoses.
METHODS: Review of hospital records and diagnostic reports. Individual cases were diagnosed by combinations of clinical assessment, skin biopsy (immunohistochemistry and transmission electron microscopy), Sanger sequencing of EB genes, and whole exome sequencing.
RESULTS: Fifty-four families with EB were registered with the clinic over this period, 41 of whom (84 patients) participated in diagnostic studies. Thirty-seven of these 41 families had consanguineous marriages; 34 had recessive forms of EB, while only seven had dominant subtypes. Recurrent mutations were observed in epidermal dystonin, transglutaminase 5, and type VII collagen.
CONCLUSIONS: The prevalence of EB in Kuwait is approximately three times that of internationally cited rates with an over-representation of autosomal recessive variants. Establishing the molecular basis of EB in Kuwait with accurate diagnostic subtyping provides a basis for determining healthcare requirements and improving patient management of EB.

PMID: 30011071 [PubMed - as supplied by publisher]

Basonuclin 1 Deficiency is a Cause of Primary Ovarian Insufficiency.

Hum Mol Genet. 2018 Jul 16;:

Authors: Zhang D, Liu Y, Zhang Z, Lv P, Liu Y, Li J, Wu Y, Zhang R, Huang Y, Xu G, Qian Y, Qian Y, Chen S, Xu C, Shen J, Zhu L, Chen K, Zhu B, Ye X, Mao Y, Bo X, Zhou C, Wang T, Chen D, Yang W, Tan Y, Song Y, Zhou D, Sheng J, Gao H, Zhu Y, Li M, Wu L, He L, Huang H

Abstract
Primary ovarian insufficiency (POI) leads to infertility and premature menopause in young women. The genetic etiology of this disorder remains unknown in most patients. Using whole-exome sequencing of a large Chinese POI pedigree, we identified a heterozygous 5 bp deletion inducing a frameshift in BNC1, which is predicted to result in nonsense mediated decay or a truncated BNC1 protein. Sanger sequencing identified another BNC1 missense mutation in four of 82 idiopathic POI patients, and the mutation was absent in 332 healthy controls. Transfection of recombinant plasmids with the frameshift mutant and separately with the missense mutant in HEK293T cells led to abnormal nuclear localization. Knockdown of BNC1 was found to reduce BMP15 and p-AKT levels, and to inhibit meiosis in oocytes. A female mouse model of the human Bnc1 frameshift mutation exhibited infertility, significantly increased serum follicle stimulating hormone, decreased ovary size and reduced follicle numbers, consistent with POI. We report haploinsufficiency of BNC1 as an etiology of human autosomal dominant POI.

PMID: 30010909 [PubMed - as supplied by publisher]