A novel compound heterozygous mutation of von Hippel-Lindau gene in a Chinese patient with erythrocytosis

Annals of Hematology -     

A novel heterozygous mutation in the NOTCH3 gene causing CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an identifiable cause of inherited stroke among young adults, characterised by diffuse leukoencephalopathy with prominent involvement of the temporal poles and external capsule. The disease is caused by mutations in the NOTCH3 gene encoding a NOTCH3 receptor protein. The clinical course is relentlessly progressive with early transient ischaemic attacks (TIA) or strokes, dementia and finally death in the mid-60s. We describe a 40-year-old patient with clinical features of CADASIL and a positive family history who was a carrier of a new mutation at the exon 4 of the NOTCH3 gene: C162R. Regardless of the distinctive clinical and neuroimaging features one of his siblings had been mistakenly diagnosed as suffering from multiple sclerosis (MS), suggesting that the disease can occasionally be misdiagnosed as MS.     

Correction to: A novel compound heterozygous mutation of von Hippel‑Lindau gene in a Chinese patient with erythrocytosis

Annals of Hematology -     

A novel,complex heterozygous mutation within Gsalpha gene in patient with McCune-Albright syndrome

McCune-Albright syndrome (MAS) is caused by embryonic somatic mutations leading to the substitution of His or Cys for Arg at amino acid 201 of the α-subunit of the signal transduction protein Gs (Gsα). The mutations have been found in many affected tissues of patients with MAS. Recently, a new missense mutation was detected in a patient with MAS, leading to the substitution of glycine for arginine at amino acid 201 of the Gsα gene, whereas no mutations have been reported at other sites in this gene. In the present study, we identified the activating mutations in the gene encoding Gsα protein in the osseous lesions of fibrous dysplasia and peripheral blood leukocyte in a 17-yr-old male patient with MAS. In addition, a heterozygous mutation encoding substitution of Arg201 of Gsα with His was found. Interestingly, we also found the other two types of mutations within the Gsα gene in the patient’s affected osseous tissue. One is a combination mutation in the same allele at codons 209 and 210 of the Gsα gene, and the other the missense mutation at codon 235.     

A novel mutation in the pendrin gene associated with Pendred's syndrome

OBJECTIVE: Pendred's syndrome is an autosomal recessive disorder characterized by goitre, sensorineural deafness and iodide organification defect. It is one of the most frequent causes of congenital deafness, accounting for about 10% of hereditary hearing loss. It is caused by mutations in the pendrin (PDS) gene, a 21 exon gene located on chromosome 7. The aim of this study was to examine an Italian family affected with Pendred's syndrome at the molecular level. PATIENTS: Thirteen subjects belonging to a family from Southern Italy were evaluated for the clinical and genetic features of Pendred's syndrome. MEASUREMENTS: Exons 2-21 of the PDS gene were amplified from peripheral leucocytes by the polymerase chain reaction; mutation analysis was performed by single strand conformation polymorphism, direct sequencing and restriction analysis. RESULTS: The index patient had the classical triad of the syndrome and harboured two mutations in the PDS gene in the form of compound heterozygosity. He was found to be heterozygous for a cytosine to adenosine mutation at nucleotide 1523 in exon 13 and for a IVS 1001 + 1G --> A mutation. The former is a novel mutation which results in a change of 508 threonine to asparagine in the putative eleventh transmembrane domain. The latter mutation in the donor splice site has already been described in other patients and is thought to lead to aberrant splicing and premature protein truncation. Three subjects who were heterozygous for one mutation had normal phenotypes. Two subjects had sensorineural deafness and were heterozygous for a single mutation. Goitre was found only in patients with Pendred's syndrome and was absent in all other individuals, albeit residing in an iodine-deficient area. CONCLUSIONS: We have identified a novel mutation in the pendrin gene causing Pendred's syndrome, and confirm that molecular analysis is a useful tool for a definitive diagnosis. This is particularly relevant in cases such as in the subjects of our family in which the clinical features might be misleading and other genetics factors might be responsible for deafness.     

A novel mutation in the ferrochelatase gene associated with erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is a hereditary disorder caused by mutations of the ferrochelatase gene. We investigated a Japanese patient with a dominant form of erythropoietic protoporphyria for a ferrochelatase mutation. Sequence analysis of the proband's ferrochelatase cDNA revealed a T to C point mutation at nucleotide 557. This mutation resulted in the replacement of Ile by Thr at amino acid position 186, a novel mutation in erythropoietic protoporphyria. An increase in ferrochelatase activity was not observed in the crude extract of E. coli over-expressing the mutant protein compared with the control, whereas a marked increase in activity was observed in that over-expressing the wild type. Prediction of the secondary structure of ferrochelatase suggested that the Ile¹⁸⁶ → Thr mutation changed the original β-sheet structure to an α helix in the region including amino acid residue of mutation. We conclude that, in this patient, the Ile¹⁸⁶ → Thr mutation had abolished enzyme activity, possibly by disrupting the secondary structure, thereby causing erythropoietic protoporphyria.     

A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations

Background

The role of mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene in chronic pancreatitis is still a matter of debate. Active SPINK1 is thought to antagonize activated trypsin. Cases of SPINK1 mutations, especially N34S, have been reported in a subset of patients with idiopathic chronic pancreatitis. However, the inheritance pattern is still unknown. Some cases with N34S heterozygosity have been reported with and without evidence for CP indicating neither an autosomal recessive nor dominant trait. Therefore SPINK1 mutations have been postulated to act as a disease modifier requiring additional mutations in a more complex genetic model. Familial hypocalciuric hypercalcemia (FHH) caused by heterozygous inactivating mutations in the calcium sensing receptor (CASR) gene is considered a benign disorder with elevated plasma calcium levels. Although hypercalcemia represents a risk factor for pancreatitis, increased rates of pancreatitis in patients with FHH have not been reported thus far.

Methods

We studied a family with a FHH-related hypercalcemia and chronic pancreatitis. DNA samples were analysed for mutations within the cationic trypsinogen (N29I, R122H) and SPINK1 (N34S) gene using melting curve analysis. Mutations within CASR gene were identified by DNA sequencing.

Results

A N34S SPINK1 mutation was found in all screened family members. However, only two family members developed chronic pancreatitis. These patients also had FHH caused by a novel, sporadic mutation in the CASR gene (518T>C) leading to an amino acid exchange (leucine->proline) in the extracellular domain of the CASR protein.

Conclusion

Mutations in the calcium sensing receptor gene might represent a novel as yet unidentified predisposing factor which may lead to an increased susceptibility for chronic pancreatitis. Moreover, this family analysis supports the hypothesis that SPINK1 mutations act as disease modifier and suggests an even more complex genetic model in SPINK1 related chronic pancreatitis.

     

A case of factor XI deficiency caused by compound heterozygous F11 gene mutation

Summary.  Inherited factor XI (FXI) deficiency is a rare autosomal recessive bleeding disorder in most populations except for Ashkenazi Jews. In this report, a 25-year-old Chinese female FXI deficiency case has been studied. Routine clotting tests showed significantly prolonged activated partial thromboplastin time (69.5 s, control 35 ± 10 s) while prothrombin time (12.3 s, control 13 ± 3 s) was normal. FXI:C and FXI:Ag were 2.6% and 2.5%, respectively, indicating that this case was cross-reacting material negative. The activities of other coagulation factors and liver function were in normal range. The DNA sequence results of the 15 exons and their boundaries of F11 gene revealed a novel G3733C missense mutation in exon 2, and a recurrent C16642T nonsense mutation in exon 8. The G3733C mutation caused G-1R substitution in FXI signal peptide, which might impair the protein's secretion and introduced a new BssSI enzyme digestion site. The C16642T mutation led a premature stop codon at amino acid position 263(Q263Term). G-1R and Q263Term compound heterozygous mutations in F11 gene were the cause of FXI deficiency for this proband. G-1R mutation was a novel F11 gene mutation causing inherited FXI deficiency.     

A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy.

Familial partial lipodystrophies (FPL) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia. Recently, lamin A/C gene mutations were found in patients with FPL, Dunnigan variety. However, the genetic basis of other phenotypes remains unknown. We studied peroxisome proliferator-activated receptor-gamma (PPARgamma) gene as a candidate gene in seven FPL patients who did not appear to have Dunnigan variety. Analysis of the coding region of PPARG revealed C to T heterozygous mutation at nucleotide 1273 in exon 6 which changes a highly conserved residue, arginine at position 425 to cysteine (R425C) in the patient FX200.21. The patient is a 64-year-old nonHispanic white woman who developed diabetes mellitus and hypertriglyceridemia at age 32 years and lipodystrophy of the extremities and face at age 50 years. She also had hirsutism. Anthropometry and whole body magnetic resonance imaging revealed marked loss of sc fat particularly from the extremities but sc truncal fat was slightly increased. None of the four unaffected family members harbored the mutation. We conclude that heterozygous, R425C, mutation in PPARG could be the molecular basis for one of the familial partial lipodystrophy phenotypes.     

A novel compound heterozygous COL4A4 mutation in a Chinese family with Alport syndrome: A care case report

Rationale:Alport syndrome (AS) is an inherited progressive renal failure, characterized by kidney disease, hearing loss, and eye abnormalities.Patient concerns:A 7-year-old male child was admitted for persistent microscopic hematuria and proteinuria.Diagnoses:Combined with clinical manifestations, laboratory testing, pathological changes of kidney and sequencing results, the patient was diagnosed as AS.Interventions:The patient was treated with ACEI and tacrolimus drugs for 2 years, but continued to have hematuria and proteinuria. Thus, a genetic analysis was performed using next-generation sequencing in four affected members from the family.Outcomes:The findings revealed triple compound heterozygous mutation of COL4A4: three novel variations, c.1045C>T (p. R349X), c.3505+1G>A (splicing), and c.2165G>A (p. G722D).Lessons:This study was novel in finding that a triple variant of the COL4A4 gene simultaneously in trans and in cis. The effects of multiple mutation sites and the type of gene mutation in AS were also underlined.     

Neonatal severe hyperparathyroidism associated with a novel de novo heterozygous R551K inactivating mutation and a heterozygous A986S polymorphism of the calcium-sensing receptor gene

INTRODUCTION: Neonatal severe hyperparathyroidism (NSHPT) is induced by inactivating mutations of human calcium-sensing receptor (CaSR). Only three heterozygous de novo inactivating mutations of CaSR causing NSHPT have been described. We report the case of a now 11-year-old boy with NSHPT and we characterize a novel inactivating mutation along with the results of some functional analyses. PATIENT AND METHODS: As a neonate the patient presented the clinical syndrome of NSHPT. At 6 years of age persisting hypercalcaemia without clinical symptoms was documented, and the patient remained completely symptom free without parathyroid surgery until his present age of 11 years. The entire coding region of the CaSR gene of the patient and his family members was sequenced. Functional investigation was performed in HEK-293 cells, transiently transfected with wild type and mutant CaSR plasmid constructs. RESULTS: Sequence analysis revealed a novel de novo heterozygous mutation at codon 551 (AGG-->AAG), predicting a change of arginine to lysine (R551K) and a known heterozygous polymorphism (A986S) on the same allele, which was inherited from the father. We demonstrated that the novel R551K mutation significantly reduced the calcium sensitivity of CaSR (EC50: from 3.38 +/- 0.62-6.10 +/- 0.83 mmol/l), which was not alleviated by the simultaneous presence of A986S polymorphism. CONCLUSIONS: We present the fourth NSHPT case induced by a novel de novo heterozygous inactivating mutation (R551K) of the CaSR gene. The disease gradually reverted to a symptomless, benign condition resembling familial hypocalciuric hypercalcaemia without any surgical intervention.     

ATP7B基因复合杂合突变合并妊娠期急性脂肪肝1例报告

<正>1 病例资料女性患者,28岁,因"停经39+6周,浮肿1个月余,血压升高2 d"于2020年9月20日入院。患者孕39+6周,正规产检。患者6年前及5年前分别顺产一女,新生儿体健,1年前人流一次,均无大出血史,体健。否认近亲婚配史及家族史。入院查体:血压142/91 mmHg, BMI 44.3 kg/m2,贫血貌,心肺未见异常,腹膨隆,腹壁浮肿,胎心率140 次/min, 双下肢对称凹陷性水肿。入院后辅助检查:     

Factors affecting preventive behaviors of Alzheimer’s disease in family members of patients with Alzheimer’s disease

As genetic factors increase the risk of Alzheimer’s disease (AD), the families of dementia patients are at risk of AD. We aimed to evaluate the factors affecting preventive behaviors of AD in family members of AD patients. Using constructed questionnaire based on the Health Belief Model (HBM) theoretical framework, this cross-sectional study investigated factors influencing preventive behaviors of AD such the intention to take AD-preventive medicines, prior experience of taking cognitive function supplements, and AD-preventive lifestyle. 147 family members of AD patients were recruited through the Korea Alzheimer’s Caregiver Association. Out of 147 participants, 94.6% had intention to take AD-preventive medicines and 46.3% had experience of taking cognitive function supplements. The intention to take AD-preventive medicines were significantly influenced by self-efficacy (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.03, 1.87) and dementia knowledge (OR 3.42, 95% CI 1.13, 10.39), whereas prior experience of cognitive function supplements was significantly associated with cue to action (OR 1.22, 95% CI 1.07, 1.40). AD-preventive lifestyle was significantly influenced by socio-demographics such as age, sex, and marital status, and the HBM factors such as perceived susceptibility, self-efficacy, and cue to action. Self-efficacy, cue to action, dementia knowledge, and perceived susceptibility were significantly associated with preventive behaviors of AD. Also, family members of dementia patients, who are at risk of dementia due to genetic factors, lifestyles, and environment factors, had high level of AD-preventive lifestyle and strong intention to take AD-preventive medicines. Further research could be suggested to understand AD-preventive behavior and intention to take AD-preventive medicines in general population.     

A novel heterozygous mutation in the glucokinase gene conferring exercise-induced symptomatic hyperglycaemia responsive to sulfonylurea

AimTo describe the atypical phenotype and genotype of an adolescent girl with symptomatic exercise-induced hyperglycaemia, responsive to sulfonylurea treatment.MethodsChart review, gene sequencing, and blinded continuous glucose monitoring (Medtronic iPro2) were used to characterise the case.ResultsA novel heterozygous mutation p.Q219x (c.655C>T) in exon 6 of the glucokinase gene (NM_000162.3) was confirmed in the patient and father. Initiation of gliclazide 20 mg twice daily was associated with resolution of symptoms and normalization of haemoglobin A1C (5.6%). Blinded continuous glucose monitoring demonstrated significantly less time spent in the hyperglycaemic range (sensor glucose > 8.0 mmol/L) when on twice daily gliclazide versus intermittent or no gliclazide (mean minutes/day with sensor glucose > 8 mmol/L: 53.6 ± 90.0 vs. 307.9 ± 246.6; P = 0.04).ConclusionsThis novel mutation in the glucokinase gene led to atypical symptomatic exercise-induced hyperglycaemia that was responsive to low dose sulfonylurea with self-reported additional benefit after reduction of carbohydrate intake. We postulate that her atypical clinical presentation was related to the intense elite-level physical activity combined with carbohydrate loading before exercise.     

A novel mutation in the KCNH2 gene associated with short QT syndrome

A gain of function mutation N588K in the KCNH2 gene that encodes HERG channels has been shown to underlie the SQT1 form of short QT syndrome (SQTS). We describe a different mutation in the KCNH2 gene in a Chinese family with clinical evidence of SQTS. A Chinese family with a markedly short QT interval (QTc = 316 ± 9 ms, n = 4) and a strong family history of sudden death was investigated. Analysis of candidate genes contributing to ventricular repolarization identified a C1853T mutation in the KCNH2 gene coding for the HERG channel, resulting in an amino acid change (T618I) that was found to 100% co-segregate with the SQTS phenotype (n = 4). Whole cell voltage clamp studies of the T618I mutation in HEK-cells demonstrated a 6-fold increase in maximum steady state current (146.1 ± 16.7 vs 23.8 ± 5.5 pA/pF) that occurred at a 20 mV more positive potential compared to the wild type channels. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT −78.6 ± 6.8 vs T618I −29.3 ± 1.7 mV). Kinetic analysis revealed slower inactivation rates of T618I but faster rates of recovery from inactivation. Quinidine (5 μM) and sotalol (500 μM) had similar inhibitory effects on steady currents measured at + 20 mV in WT and T618I but were less effective in inhibiting tail currents of mutant channels. The altered function of T618I-HERG channels suggests that this mutation in the KCNH2 gene is responsible for the SQTS phenotype in this family. Both quinidine and sotalol may be therapeutic options for patients with the T618I HERG mutation.