RÉSUMÉ
Insulin-like growth factor binding protein 4 (IGFBP4) is involved in adipogenesis, and IGFBP4 null mice have decreased body fat through decreased PPAR-γ expression. In the current study, we assessed whether variation in the IGFBP4 coding region influences body mass index (BMI) in American Indians who are disproportionately affected by obesity. Whole exome sequence data from a population-based sample of 6779 American Indians with longitudinal measures of BMI were used to identify variation in IGFBP4 that associated with BMI. A novel variant that predicts a p.Ser76Thr in IGFBP4 (Thr-allele frequency = 0.02) was identified which associated with the maximum BMI measured during adulthood (BMI 39.8 kg/m2 for Thr-allele homozygotes combined with heterozygotes vs. 36.2 kg/m2 for Ser-allele homozygotes, ß = 6.7% per Thr-allele, p = 8.0 × 10-5, adjusted for age, sex, birth-year and the first five genetic principal components) and the maximum age- and sex-adjusted BMI z-score measured during childhood/adolescence (z-score 0.70 SD for Thr-allele heterozygotes vs. 0.32 SD for Ser-allele homozygotes, ß = 0.37 SD per Thr-allele, p = 8.8 × 10-6). In vitro functional studies showed that IGFBP4 with the Thr-allele (BMI-increasing) had a 55% decrease (p = 0.0007) in FOXO-induced transcriptional activity, reflecting increased activation of the PI3K/AKT pathway mediated through increased IGF signaling. Over-expression and knock-down of IGFBP4 in OP9 cells during differentiation showed that IGFBP4 upregulates adipogenesis through PPARγ, CEBPα, AGPAT2 and SREBP1 expression. We propose that this American Indian specific variant in IGFBP4 affects obesity via an increase of IGF signaling.
Sujet(s)
Indiens d'Amérique Nord , Protéine-4 de liaison aux IGF , Animaux , Indice de masse corporelle , Humains , Indiens d'Amérique Nord/génétique , Protéine-4 de liaison aux IGF/génétique , Souris , Obésité/génétique , Récepteur PPAR gamma/génétique , Phosphatidylinositol 3-kinases/génétique , Polymorphisme de nucléotide simple , Protéines proto-oncogènes c-akt/génétique , Population d'origine amérindienneRÉSUMÉ
Clinical and biomarker phenotypic associations for carriers of protein function-altering variants may help to elucidate gene function and health effects in populations. We genotyped 1127 Strong Heart Family Study participants for protein function-altering single nucleotide variants (SNV) and indels selected from a low coverage whole exome sequencing of American Indians. We tested the association of each SNV/indel with 35 cardiometabolic traits. Among 1206 variants (average minor allele count = 20, range of 1 to 1064), ~ 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p = 8 × 10-9) associated with fasting triglycerides, which gene product is involved in macrophage lipid homeostasis. Among non-diabetic individuals, missense SNVs at four genes were associated with fasting insulin adjusted for BMI (PHIL, chr6:79,650,711, p = 2.1 × 10-6; TRPM3, rs760461668, p = 5 × 10-8; SPTY2D1, rs756851199, p = 1.6 × 10-8; and TSPO, rs566547284, p = 2.4 × 10-6). PHIL encoded protein is involved in pancreatic ß-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic ß-cells in response to glucose. A genetic risk score combining increasing insulin risk alleles of these four genes was associated with 53% (95% confidence interval 1.09, 2.15) increased odds of incident diabetes and 83% (95% confidence interval 1.35, 2.48) increased odds of impaired fasting glucose at follow-up. Our study uncovered novel gene-trait associations through the study of protein-coding variants and demonstrates the advantages of association screenings targeting diverse and high-risk populations to study variants absent in publicly available repositories.
Sujet(s)
Maladies cardiovasculaires , Diabète de type 2 , Diabète de type 2/métabolisme , Jeûne , Prédisposition génétique à une maladie , Glucose/métabolisme , Humains , Insuline/génétique , Polymorphisme de nucléotide simple , Récepteurs GABA/génétiqueRÉSUMÉ
OBJECTIVE: This study aimed to identify genetic variants enriched in Southwest American Indian (SWAI) individuals that associate with BMI. METHODS: Whole genome sequencing data (n = 296) were used to identify potentially functional variants that are common in SWAI individuals (minor allele frequency ≥10%) but rare in other ethnic groups (minor allele frequency < 0.1%). Enriched variants were tested for association with BMI in 5,870 SWAI individuals. One variant was studied using a luciferase reporter, and haplotypes that included this variant were analyzed for association with various measures of obesity (n = 917-5,870), 24-hour energy expenditure (24-h EE; n = 419), and skeletal muscle biopsy expression data (n = 207). RESULTS: A 5' untranslated region variant in cytochrome b5 type A (CYB5A), rs548402150, met the enrichment criteria and associated with increased BMI (ß = 2%, p = 0.004). Functionally, rs548402150 decreased luciferase expression by 30% (p = 0.003) and correlated with decreased skeletal muscle CYB5A expression (ß = -0.5 SD, p = 0.0008). Combining rs548402150 with two splicing quantitative trait loci in CYB5A identified a haplotype carried almost exclusively in SWAI individuals that associated with increased BMI (ß = 3%, p = 0.0003) and decreased CYB5A expression, whereas the most common haplotype in all ethnic groups associated with lower BMI and percentage of body fatness, increased 24-h EE, and increased CYB5A expression. CONCLUSIONS: Further studies on the effects of CYB5A on 24-h EE and BMI may provide insights into obesity-related physiology.
Sujet(s)
Cytochromes b5 , Obésité , Indice de masse corporelle , Cytochromes b5/génétique , Cytochromes b5/métabolisme , Fréquence d'allèle , Humains , Obésité/génétique , Polymorphisme de nucléotide simple , Population d'origine amérindienneRÉSUMÉ
AIMS: Hormone sensitive lipase (HSL), encoded by the LIPE gene, is involved in lipolysis. Based on prior animal and human studies, LIPE was analysed as a candidate gene for the development of type 2 diabetes (T2D) in a community-based sample of American Indians. MATERIALS AND METHODS: Whole-exome sequence data from 6782 participants with longitudinal clinical measures were used to identify variation in LIPE. RESULTS: Amongst the 16 missense variants identified, an Arg611Cys variant (rs34052647; Cys-allele frequency = 0.087) significantly associated with T2D (OR [95% CI] = 1.38 [1.17-1.64], p = 0.0002, adjusted for age, sex, birth year, and the first five genetic principal components) and an earlier onset age of T2D (HR = 1.22 [1.09-1.36], p = 0.0005). This variant was further analysed for quantitative traits related to T2D. Amongst non-diabetic American Indians, those with the T2D risk Cys-allele had increased insulin levels during an oral glucose tolerance test (0.07 SD per Cys-allele, p = 0.04) and a mixed meal test (0.08 log10 µU/ml per Cys-allele, p = 0.003), and had increased lipid oxidation rates post-absorptively and during insulin infusion (0.07 mg [kg estimated metabolic body size {EMBS}]-1 min-1 per Cys-allele for both, p = 0.01 and 0.009, respectively), compared to individuals with the non-risk Arg-allele. In vitro functional studies showed that cells expressing the Cys-allele had a 17.2% decrease in lipolysis under isoproterenol stimulation (p = 0.03) and a 21.3% decrease in lipase enzyme activity measured by using p-nitrophenyl butyrate as a substrate (p = 0.04) compared to the Arg-allele. CONCLUSION: The Arg611Cys variant causes a modest impairment in lipolysis, thereby affecting glucose homoeostasis and risk of T2D.
Sujet(s)
Diabète de type 2 , Sterol Esterase , Animaux , Diabète de type 2/génétique , Diabète de type 2/métabolisme , Humains , Insuline/métabolisme , Lipolyse/génétique , Sterol Esterase/génétique , Sterol Esterase/métabolisme , Population d'origine amérindienneRÉSUMÉ
While the samples and data from the Pima Indians of the Gila River Indian Community have been included in many international HLA workshops and conferences and have been the focus of numerous population reports and the source of novel alleles at the classical HLA loci, they have not been studied for the non-classical loci. In order to expand our HLA-disease association studies, we typed over 300 whole genome sequences from full Pima heritage members, controlled for first degree relationship, and employed recently developed computer algorithms to resolve HLA alleles. Both classical-HLA-A, -B, and -C- and non-classical- HLA-E, -F, -G, -J, -L, -W, -Y, -DPA2, -DPB2, -DMA, -DMB, -DOA, -DRB2, -DRB9, TAP1- loci were typed at the 4-field level of resolution. We present allele and selected haplotype frequencies, test the genotype distributions for population structure, discuss the issues that are created for tests of Hardy-Weinberg equilibrium over the four sample spaces of high resolution HLA typing, and address the implications for the evolution of non-classical pseudogenes that are no longer expressed in a phenotype subject to natural selection.
Sujet(s)
Population d'origine amérindienne , Génotype , Antigènes HLA/génétique , Algorithmes , Arizona , Évolution moléculaire , Fréquence d'allèle , Locus génétiques , Génétique des populations , Séquençage nucléotidique à haut débit , Test d'histocompatibilité , Humains , Séquençage du génome entierRÉSUMÉ
OBJECTIVE: In an ongoing effort to identify the genetic variation that contributes to obesity in American Indians, known Bardet-Biedl syndrome (BBS) genes were analyzed for an effect on BMI and leptin signaling. METHODS: Potentially deleterious variants (Combined Annotation Dependent Depletion score > 20) in BBS genes were identified in whole-exome sequence data from 6,851 American Indians informative for BMI. Common variants (detected in ≥ 10 individuals) were analyzed for association with BMI; rare variants (detected in < 10 individuals) were analyzed for mean BMI of carriers. Functional assessment of variants' effect on signal transducer and activator of transcription 3 (STAT3) activity was performed in vitro. RESULTS: One common variant, rs59252892 (Thr549Ile) in BBS9, was associated with BMI (P = 0.0008, ß = 25% increase per risk allele). Among rare variants for which carriers had severe obesity (mean BMI > 40 kg/m2 ), four were in BBS9. In vitro analysis of BBS9 found the Ile allele at Thr549Ile had a 20% increase in STAT3 activity compared with the Thr allele (P = 0.01). Western blot analysis showed the Ile allele had a 15% increase in STAT3 phosphorylation (P = 0.006). Comparable functional results were observed with Ser545Gly and Val209Leu but not Leu665Phe and Lys810Glu. CONCLUSIONS: Potentially functional variants in BBS genes in American Indians are reported. However, functional evidence supporting a causal role for BBS9 in obesity is inconclusive.
Sujet(s)
Syndrome de Bardet-Biedl/génétique , Exome/génétique , Obésité/génétique , Femelle , Humains , Mâle , Population d'origine amérindienneRÉSUMÉ
BACKGROUND: Obesity and energy expenditure (EE) are heritable and genetic variants influencing EE may contribute to the development of obesity. We sought to identify genetic variants that affect EE in American Indians, an ethnic group with high prevalence of obesity. METHODS: Whole-exome sequencing was performed in 373 healthy Pima Indians informative for 24-hour EE during energy balance. Genetic association analyses of all high-quality exonic variants (≥5 carriers) was performed, and those predicted to be damaging were prioritized. RESULTS: Rs752074397 introduces a premature stop codon (Cys264Ter) in DAO and demonstrated the strongest association for 24-hour EE, where the Ter allele associated with substantially lower 24-hour EE (mean lower by 268 kcal/d) and sleeping EE (by 135 kcal/d). The Ter allele has a frequency = 0.5% in Pima Indians, whereas is extremely rare in most other ethnic groups (frequency < 0.01%). In vitro functional analysis showed reduced protein levels for the truncated form of DAO consistent with increased protein degradation. DAO encodes D-amino acid oxidase, which is involved in dopamine synthesis which might explain its role in modulating EE. CONCLUSION: Our results indicate that a nonsense mutation in DAO may influence EE in American Indians. Identification of variants that influence energy metabolism may lead to new pathways to treat human obesity. CLINICAL TRIAL REGISTRATION NUMBER: NCT00340132.
Sujet(s)
Population d'origine amérindienne/génétique , Codon non-sens , D-amino-acid oxidase/génétique , Métabolisme énergétique/génétique , Adolescent , Adulte , Allèles , Exome , Femelle , Fréquence d'allèle , Hyperglycémie provoquée , Humains , Mâle , Adulte d'âge moyen , Obésité/génétique , , Jeune adulteRÉSUMÉ
Applying exome sequencing to populations with unique genetic architecture has the potential to reveal novel genes and variants associated with traits and diseases. We sequenced and analyzed the exomes of 6,716 individuals from a Southwestern American Indian (SWAI) population with well-characterized metabolic traits. We found that the SWAI population has distinct allelic architecture compared to populations of European and East Asian ancestry, and there were many predicted loss-of-function (pLOF) and nonsynonymous variants that were highly enriched or private in the SWAI population. We used pLOF and nonsynonymous variants in the SWAI population to evaluate gene-burden associations of candidate genes from European genome-wide association studies (GWASs) for type 2 diabetes, body mass index, and four major plasma lipids. We found 19 significant gene-burden associations for 11 genes, providing additional evidence for prioritizing candidate effector genes of GWAS signals. Interestingly, these associations were mainly driven by pLOF and nonsynonymous variants that are unique or highly enriched in the SWAI population. Particularly, we found four pLOF or nonsynonymous variants in APOB, APOE, PCSK9, and TM6SF2 that are private or enriched in the SWAI population and associated with low-density lipoprotein (LDL) cholesterol levels. Their large estimated effects on LDL cholesterol levels suggest strong impacts on protein function and potential clinical implications of these variants in cardiovascular health. In summary, our study illustrates the utility and potential of exome sequencing in genetically unique populations, such as the SWAI population, to prioritize candidate effector genes within GWAS loci and to find additional variants in known disease genes with potential clinical impact.
Sujet(s)
Exome/génétique , Prédisposition génétique à une maladie/génétique , Indiens d'Amérique Nord/génétique , Polymorphisme de nucléotide simple/génétique , Allèles , Indice de masse corporelle , Femelle , Génétique des populations/méthodes , Étude d'association pangénomique/méthodes , Humains , Mâle , Phénotype , États du Sud-Ouest des États-UnisRÉSUMÉ
BACKGROUND/OBJECTIVES: Nighttime eating (NE) behavior has a genetic component and predicts weight gain. We hypothesized that some genetic variants, which affect NE would also show an effect on body mass index (BMI). We aimed to determine which known BMI variants associate with NE in Southwestern American Indians (SWAIs), who are at elevated risk for obesity. METHODS: Known BMI variants from the GIANT-UK Biobank meta-analysis (N = 700,000) were analysed in SWAIs characterized for NE during an inpatient 3-day protocol. Variants were analysed for association with NE using whole-genome sequence data from 50 SWAIs (23 cases and 27 controls) and selected variants were genotyped in an additional 32 SWAIs (13 NE cases and 19 controls). Variants associated with NE in a meta-analysis of the two SWAI samples were further analysed for association with nightly caloric intake and functionality in hypothalamus, pituitary, and adrenal tissues. RESULTS: Variants were identified where the allele that associated with increased BMI in the GIANT-UK Biobank meta-analysis (P ≤ 1 × 10-8) also had a P < 0.01 for increased NE in the SWAI meta-analysis. These variants were captured by six tagSNPs. Comparison of the nightly calorie intake by genotype and eQTL data from relevant tissues highlighted rs3753612 upstream of HCRTR1. CONCLUSIONS: Our strategy led to the HCRTR1 locus, which has previously been linked to sleep regulation and feeding. Although this is an intriguing candidate gene for NE, further studies in larger samples and different populations are required to validate the role of HCRTR1 in NE.
Sujet(s)
Population d'origine amérindienne , Indiens d'Amérique Nord , Indice de masse corporelle , Comportement alimentaire , Prédisposition génétique à une maladie , Génotype , Humains , Indiens d'Amérique Nord/génétique , Récepteurs des orexines , Polymorphisme de nucléotide simpleRÉSUMÉ
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease eventually leading to death from respiratory failure. Recessive inheritance is very rare. Here, we describe the clinical findings in a consanguineous family with five men afflicted with recessive ALS and the identification of the homozygous mutation responsible for the disorder. The onset of the disease ranged from 12 to 35 years of age, with variable disease progressions. We performed clinical investigations including metabolic and paraneoplastic screening, cranial and cervical imaging, and electrophysiology. We mapped the disease gene to 9p21.1-p12 with a LOD score of 5.2 via linkage mapping using genotype data for single-nucleotide polymorphism markers and performed exome sequence analysis to identify the disease-causing gene variant. We also Sanger sequenced all coding sequences of SIGMAR1, a gene reported as responsible for juvenile ALS in a family. We did not find any mutation in SIGMAR1. Instead, we identified a novel homozygous missense mutation p.(His705Arg) in GNE which was predicted as damaging by online tools. GNE has been associated with inclusion body myopathy and is expressed in many tissues. We propose that the GNE mutation underlies the pathology in the family.
Sujet(s)
Sclérose latérale amyotrophique/génétique , Mutation faux-sens/génétique , Mutation/génétique , Phosphotransferases (Alcohol Group Acceptor)/génétique , Adulte , Asiatiques/génétique , Cartographie chromosomique , Exons/génétique , Génotype , Humains , Mâle , Adulte d'âge moyen , Phénotype , Polymorphisme de nucléotide simple/génétiqueRÉSUMÉ
In two brothers born to consanguineous parents, we identified an unusual neurological disease that manifested with ataxia, psychomotor retardation, cerebellar and cerebral atrophy, and leukodystrophy. Via linkage analysis and exome sequencing, we identified homozygous c.2801C>T (p.(Ser934Leu)) in POLR1A (encoding RPA194, largest subunit of RNA polymerase I) and c.511C>T (p.(Arg171Trp)) in OSBPL11 (encoding oxysterol-binding protein-like protein 11). Although in silico analysis, histopathologic evidence and functional verification indicated that both variants were deleterious, segregation with the patient phenotype established that the POLR1A defect underlies the disease, as a clinically unaffected sister also was homozygous for the OSBPL11 variant. Decreased nucleolar RPA194 was observed in the skin fibroblasts of only the affected brothers, whereas intracellular cholesterol accumulation was observed in the skin biopsies of the patients and the sister homozygous for the OSBPL11 variant. Our findings provide the first report showing a complex leukodystrophy associated with POLR1A. Variants in three other RNA polymerase subunits, POLR1C, POLR3A and POLR3B, are known to cause recessive leukodystrophy similar to the disease afflicting the present family but with a later onset. Of those, POLR1C is also implicated in a mandibulofacial dysostosis syndrome without leukodystrophy as POLR1A is. This syndrome is absent in the family we present.
Sujet(s)
Ataxie/génétique , DNA-directed RNA polymerases/génétique , Incapacités de développement/génétique , Leucoencéphalopathies/génétique , Mutation faux-sens , Adulte , Ataxie/diagnostic , Cellules cultivées , Enfant , Cholestérol/métabolisme , DNA-directed RNA polymerases/métabolisme , Incapacités de développement/diagnostic , Femelle , Fibroblastes/métabolisme , Homozygote , Humains , Leucoencéphalopathies/diagnostic , Mâle , Pedigree , Récepteurs aux stéroïdes/génétique , Récepteurs aux stéroïdes/métabolisme , Fratrie , SyndromeRÉSUMÉ
We present two PHO siblings having a novel homozygous truncating mutation in HPGD. The purpose of the study was to attempt medical treatment, and to find the HPGD mutation causing the disease, in a 22-year old Turkish male and his 23-year old sister afflicted with primary hypertrophic osteoarthropathy (PHO). In combination with NSAIDs and colchicine, treatment with sulfasalazine was started in both cases, and methotrexate was added to the treatment regimen of the female patient at the end of the first year. The patients were found to be typical PHO. Ultrasonographic examination of the joints revealed synovitis and inflammation by B mode and power Doppler ultrasonography. Joint symptoms responded to sulfasalazine treatment in both patients. However, after the addition of methotrexate, the female patient had better remission. All exons of HPGD, the known disease gene, were analyzed by Sanger sequencing. A homozygous 2-bp deletion (c.310_311delCT or p.L104AfsX3) was identified. Seven relatives carrying the mutation in the heterozygous state were examined and none was found affected. Although not specific for this disease, skin, soft tissue and joint ultrasonography can be helpful for evaluation of the musculoskeletal findings in the patients.
Sujet(s)
Hydroxyprostaglandine dehydrogenases/génétique , Mutation faux-sens , Pachydermopériostose/génétique , Femelle , Prédisposition génétique à une maladie , Humains , Mâle , Pedigree , Jeune adulteRÉSUMÉ
IMPORTANCE: A new form of cone-rod dystrophy (CORD) is described and the gene responsible for the disease is identified. OBJECTIVE: To clinically evaluate 4 patients and 5 control relatives, perform disease gene mapping, and identify the gene defect responsible for CORD. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational case series of 13 members of a consanguineous family and 113 unrelated control individuals. INTERVENTIONS: Clinical investigations included eye examination with color fundus and autofluorescent imaging, spectral-domain optical coherence tomography, and electrophysiologic measurements. Linkage mapping was performed using single-nucleotide polymorphism genotype data. Candidate genes were analyzed for mutations via Sanger sequencing. MAIN OUTCOMES AND MEASURES: Clinical diagnosis of CORD, disease gene mapping, and mutation identification. RESULTS: The onset of CORD occurred in early childhood. The clinical phenotype was typical CORD with photophobia, decreased central vision, and dyschromatopsia. In all patients, a disrupted inner segment/outer segment line and the external limiting membrane were noted as a single blurry line at the central fovea, and the cone outer segment tip line was absent. In the midperipheral retina, the rod inner segment/outer segment line was disrupted and blurry, and the rod outer segment tip line was absent. Cone response was nonrecordable in all patients, whereas rod response was nonrecordable in the eldest patient and subnormal in the others. The Arden Index was abnormal in the youngest patient and flat in the others. The disease gene mapped to a less than 2-megabase recessive locus at 12q21.33 with a logarithm of odds score of 3.92. At the locus, we identified a homozygous missense POC1B p.R106P mutation that was predicted as damaging by online tools. CONCLUSIONS AND RELEVANCE: POC1B is a novel gene for a new disease typical of CORD except that patients did not report night blindness. The clinical course was slowly progressive. Screening for POC1B mutation could benefit families afflicted with CORD.
Sujet(s)
Protéines du cycle cellulaire/génétique , Gènes récessifs/génétique , Mutation faux-sens , Rétinite pigmentaire/génétique , Adolescent , Adulte , Cartographie chromosomique , Chromosomes humains de la paire 12/génétique , Consanguinité , Analyse de mutations d'ADN , Électrorétinographie , Femelle , Humains , Mâle , Adulte d'âge moyen , Pedigree , Phénotype , Rétinite pigmentaire/diagnostic , Tomographie par cohérence optiqueRÉSUMÉ
Orofacial clefts are congenital defects that vary widely in type and severity, and can occur in isolation or in association with a variety of other defects. Herein, we describe a consanguineous family afflicted with a unique form of orofacial clefting manifesting as a facial midline defect that also involves mandibular and maxillary structures. All four affected sibs had median clefts of the upper and lower lips, tooth misalignment, and poor oral hygiene. Linkage analysis of 17 family members identified a 15.3-Mb pair recessive locus at 1p31 with a LOD score of 3.63. To the best of our knowledge, this is, to date, the first locus reported for facial midline clefting and the first recessive locus for an isolated orofacial defect. The locus harboured a novel intergenic deletion of 273 164 bp, for which all fully affected sibs were homozygous. We did not note any potentially pathogenic gene variant at the 1p31 locus via exome-sequencing analysis. The identified deletion could be harbouring a regulatory element for the gene associated with the orofacial defect. The best candidate for the putative target gene is LHX8, located 49 149 bp upstream of the deletion. The gene is known to be associated with facial development in several animals. Four other family members had a subclinical phenotype--a simple notch in the lower lip or an increase in the interdental distance between the lower incisors--indicative of very low-level expression of the trait.
Sujet(s)
Chromosomes humains de la paire 1/génétique , Bec-de-lièvre/génétique , Consanguinité , Délétion de gène , Homozygote , Adolescent , Enfant d'âge préscolaire , Femelle , Locus génétiques , Humains , Protéines à homéodomaine LIM/génétique , Lod score , Mâle , Facteurs de transcription/génétique , Jeune adulteRÉSUMÉ
BACKGROUND: Infantile neuroaxonal dystrophy (INAD) is a recessive disease that results in total neurological degeneration and death in childhood. PLA2G6 mutation is the underlying genetic defect, but rare genetic heterogeneity has been demonstrated. One of the five families we studied did not link to PLA2G6 locus, and in the family one of the two affected siblings additionally had atypical features including facial dysmorphism, pectus carinatum, scoliosis, pes varus, zygodactyly and bilateral cryptorchidism as well as cerebellar atrophy, as previously reported. METHODS: Sural biopsy was investigated by electron microscopy. PLA2G6 was screened for mutations by Sanger sequencing. In the mutation-free family, candidate disease loci were found via linkage analysis using data from single nucleotide polymorphism genome scans. Exome sequencing was applied to find the variants at the loci. RESULTS: PLA2G6 mutations were identified in four families including the one with an unusually severe phenotype that led to death within the first 2 years of life. In the remaining family, seven candidate loci totalling 15.2 Mb were found and a homozygous truncating mutation p.Q642X was identified in NALCN at 13q32.3. The patients are around 20-years-old. CONCLUSIONS: NALCN is the gene responsible for INAD with facial dysmorphism. The patients have lived to adulthood despite severe growth and neuromotor retardation. NALCN forms a voltage-independent ion channel with a role in the regulation of neuronal excitability. Our findings broaden the spectrum of genes associated with neuroaxonal dystrophy. Testing infants with idiopathic severe growth retardation and neurodegeneration for NALCN mutations could benefit families.
Sujet(s)
Face/malformations , Dystrophies neuroaxonales/génétique , Canaux sodiques/génétique , Adolescent , Enfant , Femelle , Humains , Nourrisson , Canaux ioniques , Mâle , Protéines membranaires , Mutation , Dystrophies neuroaxonales/anatomopathologie , PhénotypeRÉSUMÉ
Familial parkinson's disease is both clinically and genetically heterogeneous. By mapping the disease locus with a lod score of 5.13 to a < 3.5 Mbp region at 1p31.3 in a consanguineous family and subsequent exome sequencing analysis, we identified homozygous truncating mutation p.Q734X in DNAJC6. Four members of the family were afflicted with juvenile parkinsonism that presented with mental retardation, pyramidal signs and epilepsy, as well as varying degrees of a progressive neurological disease. Recently a splicing mutation in the same gene was reported in two brothers with juvenile parkinsonism that was not L-Dopa responsive and not accompanied by pyramidal signs or mental retardation. Also, an 80-kb deletion that included DNAJC6 sequences was identified in a boy reported as having obesity, epilepsy and mental retardation but not any signs of parkinsonism. The phenotype of our study family resembles both of those families, which among themselves do not share any clinical features. Our findings further establish DNAJC6 as a juvenile parkinsonism gene, and expand the spectrums of the parkinsonism phenotype and DNAJC6 mutation. DNAJC6 encodes the neuronal co-chaperone auxilin. We found that its transcript is highly significantly more abundant in brain as compared to the non-neural tissues assayed.
Sujet(s)
Prédisposition génétique à une maladie/génétique , Protéines du choc thermique HSP40/génétique , Syndromes parkinsoniens/génétique , Adolescent , Adulte , Consanguinité , Analyse de mutations d'ADN , Femelle , Génotype , Humains , Mâle , Mutation , Pedigree , Phénotype , Jeune adulteRÉSUMÉ
We report two siblings that presented hypotonia and very early-onset parkinsonism. Homozygosity mapping using SNP genome scan data identified a candidate locus that was 12.2 Mega base pairs. By exome sequencing, we found a homozygous five-nucleotide deletion (c.448_452delAGAAC) in gene Sepiapterin Reductase (SPR). The mutation is predicted to lead to premature translational termination. Sepiapterin reductase deficiency (SRD) is a recently recognized dopa-responsive dystonia. Our findings show that SRD can manifest as early-onset parkinsonism, widening the spectrum of the disease phenotype and adding to the genetic heterogeneity of the disease.
Sujet(s)
Alcohol oxidoreductases/génétique , Mutation avec décalage du cadre de lecture , Délétion de gène , Homozygote , Syndromes parkinsoniens/génétique , Adolescent , Adulte , Facteurs âges , Enfant , Femelle , Humains , Mâle , Adulte d'âge moyen , Syndromes parkinsoniens/diagnosticRÉSUMÉ
Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity in the lower limbs. They are clinically heterogeneous, and pure forms as well as complicated forms with other accompanying clinical findings are known. HSPs are also genetically heterogeneous. We performed clinical and genetic studies in a consanguineous family with five affected members. A genome scan using 405 microsatellite markers for eight members of the family identified candidate gene loci, and subsequent fine mapping in 16 members identified the gene locus responsible for the HSP. The clinical manifestations were very early onset spastic paraplegia (SPG) accompanied by mental retardation and ocular signs. The gene locus was identified as the interval 102.05-106.64 Mbp on chromosome 10. Gene MRPL43 was analyzed in the patients. No mutation but high levels of mRNA were detected. We have mapped a novel autosomal recessive complicated form of HSP (SPG45) to a 4.6-Mbp region at 10q24.3-q25.1 with multipoint logarithm of odds scores >4.5.