Type II familial synpolydactyly: report on two families with an emphasis on variations of expression.
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ABSTRACT:
SUBMITTER: Al-Qattan MM
PROVIDER: S-EPMC3039497 | biostudies-other | 2011 Jan
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Mutations of the WFS1 gene are responsible for most cases of Wolfram syndrome (WS), a rare, recessively inherited neurodegenerative disorder characterized by juvenile-onset non-autoimmune diabetes mellitus and optic atrophy. Variants of WFS1 are also associated with non-syndromic hearing loss and type-2 diabetes mellitus (T2DM). Our study adds to literature significant associations between WS and T2DM. CASE PRESENTATION:In this study, we analyzed the clinical and genetic data of two families with high prevalence of WS and T2DM. Genetic linkage analysis and DNA sequencing were exploited to identify pathogenic variants. One novel pathogenic variant (c.2243-2244insC) and one known pathogenic (c.1232_1233delCT) (frameshift) variant were identified in exon eight of WFS1 gene. CONCLUSIONS:The mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutation. Our results reveal the value of molecular analysis of WFS1 in the improvement of clinical diagnostics for WS. This study also confirms the role of WFS1 in T2DM.
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Project description:Introduction and aimType 3 Familial Partial Lipodystrophy (FPLD3) is a rare metabolic disease related to pathogenic PPARG gene variants. FPLD3 is characterized by a loss of fatty tissue in the upper and lower limbs, hips, and face. FPLD3 pathophysiology is usually associated with metabolic comorbidities such as type 2 diabetes, insulin resistance, hypertriglyceridemia, and liver dysfunction. Here, we clinically and molecularly characterized FPLD3 patients harboring novel PPARG pathogenic variants.Materials and methodsLipodystrophy-suspected patients were recruited by clinicians from an Endocrinology Reference Center. Clinical evaluation was performed, biological samples were collected for biochemical analysis, and DNA sequencing was performed to define the pathogenic variants associated with the lipodystrophic phenotype found in our clinically diagnosed FPLD subjects. Bioinformatics predictions were conducted to characterize the novel mutated PPARγ proteins.ResultsWe clinically described FPLD patients harboring two novel heterozygous PPARG variants in Brazil. Case 1 had the c.533T > C variant, which promotes the substitution of leucine to proline in position 178 (p.Leu178Pro), and cases 2 and 3 had the c.641 C > T variant, which results in the substitution of proline to leucine in the position 214 (p.Pro214Leu) at the PPARγ2 protein. These variants result in substantial conformational changes in the PPARγ2 protein.ConclusionTwo novel PPARG pathogenic variants related to FPLD3 were identified in a Brazilian FPLD cohort. These data will provide new epidemiologic data concerning FPLD3 and help understand the genotype-phenotype relationships related to the PPARG gene.
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Project description:Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease resulting from resistance to the action of adrenocorticotropic hormone (ACTH) on the adrenal cortex, which leads to isolated glucocorticoid deficiency with normal mineralocorticoid secretion. It may present in infancy or early childhood with hyperpigmentation, failure to thrive, recurrent infections, hypoglycemic attacks and convulsions that may result in coma or death. Laboratory investigations reveal low cortisol and androgen levels with high ACTH associated with normal reninaldosterone axis. The disorder may be caused by mutations in the gene of ACTH receptor (MC2R), or mutations in the newly described melanocortin- 2 receptor accessory protein (MRAP) namely, FGD type 1 and FGD type 2, respectively. Twenty five percent of FGD cases are due to the mutations of the ACTH receptor, while FGD type 2 accounts for approximately 15-20% of FGD cases. Here, we report a six-month-old male infant, who presented with recurrent hypoglycemic convulsions. Serum hormone analysis showed low cortisol and androgen levels associated with a high ACTH concentration. No mutation was found in the NR0B1 and MC2R genes excluding congenital adrenal hypoplasia and FGD type 1. We found a homozygous deletion (c. 106+1delG) in intron 3 of MRAP gene. To our knowledge, this is the first Turkish patient reported with FGD type 2 due to a known MRAP mutation.
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Project description:Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or Vitamin D metabolism. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of Vitamin D biosynthesis and action, such as Vitamin D-dependent rickets Type 1A, Type 1B, Type 2A (VDDR2A) and Type 2B. The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets). VDDR2A is a rare autosomal recessive disorder caused by mutation in the Vitamin D receptor gene, leading to end-organ resistance to 1,25(OH)2 Vitamin D3. It clinically represents growth retardation presenting in the 1st year of life and frequently associated with alopecia totalis, which differentiates it from VDDR Type 1. Due to target organ resistance, its response to Vitamin D is poor. We report two cases of familial VDDR2A, with alopecia and oral manifestations.
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Project description:BACKGROUND:Generalized gingival fibromatosis is characterized by a progressive overgrowth of the gingiva, which can be caused by a variety of factors. According to these factors, it can be defined as hereditary gingival fibromatosis, non-familial gingival fibromatosis or drug-induced gingival fibromatosis. Non-familial gingival fibromatosis is a rare entity that needs to be documented. CASE PRESENTATION:Here, we describe two cases of Chinese non-familial gingival fibromatosis. A six-year-old girl and a five-year-old boy presented with generalized gingival overgrowth. Clinical appearance, histological examination, and family history lead to the diagnosis of non-familial gingival fibromatosis. Real time PCR was performed to examine the expression of the ?2-integrin gene, ITGA2, and identified decreased expression of ITGA2 in the gingiva of patients compared to both their parents and healthy volunteers. This is the first evidence that suggests a role for ITGA2 in non-familial gingival fibromatosis. CONCLUSION:Our findings provide evidence that altered cell-matrix interactions via collagen receptors, such as ?2-integrin, may play a role in non-familial gingival fibromatosis. Thus, targeting collagen receptors might be an attractive target for the treatment of gingival fibromatosis.
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Project description:Benign familial neonatal convulsion is a rare autosomal dominant inherited epilepsy syndrome characterized by unprovoked seizures in the first few days of life, normal psychomotor development, and a positive intergenerational family history of neonatal seizures. Over 90% of the affected individuals have inherited causal mutations in KCNQ2, which encodes for the potassium voltage-gated channel subfamily Q, member 2. Mutations in KCNQ2 are also associated with a severe neonatal encephalopathy phenotype associated with poor seizure control and neurodevelopmental deficits. The authors report the clinical presentations, response to medication, and intrafamilial phenotypic variability in 2 families with benign familial neonatal convulsions, carrying previously unreported heterozygous missense mutations, c.1066C>G (p.Leu356Val) and c.1721G<A (p.Gly574Asp), in KCNQ2. The cases reported herein suggest that inherited missense mutations in KCNQ2 can be associated with an intermediate phenotype and illustrate the challenges associated with prognosis and counselling for individuals with inherited missense mutations in KCNQ2.
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Project description:PurposeTo investigate the clinical features and disease-causing mutations in two Chinese families with familial exudative vitreoretinopathy (FEVR).MethodsClinical data and genomic DNA were collected for patients with FEVR. The coding exons and adjacent intronic regions of FZD4, LRP5, TSPAN12, and NDP were amplified with PCR, and the resulting amplicons were analyzed with Sanger sequencing. Wild-type and mutant LRP5 proteins were assayed for the Norrin/β-catenin pathway by luciferase reporter assays.ResultsTwo novel heterozygous mutations in the LRP5 gene were identified in two relatives--p.A422T and p.L540P. Typical FEVR fundus change and mild reduced bone mineral density (BMD) was found in the two patients and the affected parent. In the luciferase studies, both p.A422T and p.L540P mutants displayed a significant reduction of the luciferase activity in SuperTopFlash (STF) cells in response to Norrin (87% reduction for p.A422T and 97% reduction for p.L540P). Both patients had an additional LRP5 sequence change (p.Q816P in Patient 1 from the unaffected mother and p.T852M in Patient 2 verified as a new mutation). Luciferase assay showed no reduction for p.Q816P and 94.9% reduction for the new mutation p.T852M, suggesting that p.Q816P may be not pathogenic and p.T852M may be pathogenic.ConclusionsOur findings demonstrated two new novel LRP5 mutations in Chinese patients with FEVR and mild reduced BMD. They emphasize the complexity of FEVR mutations and phenotypes.
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Project description:There are recent reports of associations of variants in the HPDL gene with a hereditary neurological disease that presents with a wide spectrum of clinical severity, ranging from severe neonatal encephalopathy with no psychomotor development to adolescent-onset uncomplicated spastic paraplegia. Here, we report two probands from unrelated families presenting with severe and intermediate variations of the clinical course. A homozygous variant in the HPDL gene was detected in each proband; however, there was no known parental consanguinity. We also highlight reductions in citrate synthase and mitochondrial complex I activity detected in both probands in different tissues, reflecting the previously proposed mitochondrial nature of disease pathogenesis associated with HPDL mutations. Further, we speculate on the functional consequences of the detected variants, although the function and substrate of the HPDL enzyme are currently unknown.
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Project description:IntroductionIdiopathic pulmonary fibrosis (IPF), a chronic progressive interstitial lung disease (ILD), Occasionally, IPF occurs in families. Familial interstitial lung disease has been reported worldwide, limited information is available on the disease among Indian patients.Case presentationA 59-year-old woman presented with a 2-year history of progressive dyspnoea. Based on clinical and radiological features, our patient was diagnosed with idiopathic pulmonary fibrosis. Several family members of her first and second generations had died from respiratory failure. Her sister also diagnosed as IPF based on typical High resolution computed tomography (HRCT) finding though she was asymptomatic and came for screening. In addition, another male patient also had similar history and diagnosed as familial IPF based on HRCT and genetic testing in spite of significant occupational exposure. Genetic study revealed SFTPA1 gene was associated with susceptibility to idiopathic pulmonary fibrosis.ConclusionOur report illustrates that asymptomatic screening of family member can uncover such a serious disease in patients with familial interstitial fibrosis. Otherwise, clinical, radiological, and histological features are indistinguishable from those of sporadic cases. Furthermore, our work highlights the importance of compiling a thorough family history in individuals presenting with cough and dyspnoea, particularly in younger patients identified with idiopathic pulmonary fibrosis.
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