A new mutation (G51C) in the iron-responsive element (IRE) of L-ferritin associated with hyperferritinaemia-cataract syndrome decreases the binding affinity of the mutated IRE for iron-regulatory proteins

Hereditary hyperferritinaemia-cataract syndrome is an autosomal dominant disorder characterized by a constitutively increased synthesis of L-ferritin in the absence of iron overload. The disorder is associated with point mutations in the iron-responsive element (IRE) of L-ferritin mRNA. We report a new mutation, G51C, identified in two members of a Canadian family, presenting a moderate increase in serum ferritin and a clinically silent bilateral cataract. Gel retardation assays showed that the binding of the mutated IRE to iron-regulatory proteins (IRPs) was reduced compared with the wild type. Structural modelling predicted that the G51C induces a rearrangement of base pairing at the lateral bulge of the IRE structure which is likely to modify IRE conformation.     

A point mutation in the iron-responsive element of the L-ferritin in a family with hereditary hyperferritinemia cataract syndrome.

BACKGROUND: Hereditary hyperferritinemia cataract syndrome is an autosomal dominant condition that is characterized by a high serum ferritin level and bilateral early-onset cataracts in the absence of iron overload. The genetic abnormality is identified as a mutation in the 5' regulatory region of the L-ferritin messenger RNA known as the iron-responsive element (IRE). The IRE controls ferritin synthesis in response to cytoplasmic iron pools by interacting with regulatory proteins called iron responsive proteins. Mutations in the IRE decrease its affinity for iron responsive proteins, leading to the constitutive synthesis of L-ferritin which results in hyperferritinemia and the intracellular accumulation of ferritin in the lens and eventual cataract formation. PATIENTS AND METHODS: A 22-year-old woman who was being investigated for hyperferritinemia was diagnosed with hereditary hyperferritinemia cataract syndrome after an extensive workup, including genetic testing for hemochromatosis and a liver biopsy to rule out iron overload. She developed anemia with phlebotomy treatments and subsequently developed symptomatic cataracts. The pedigree of her family affected with cataracts was consistent with an autosomal dominant transmission pattern. DNA was extracted from peripheral leukocytes of eight family members, four of whom were affected by cataracts. Polymerase chain reaction amplification of the 5' region of the L-ferritin gene was performed and a heterozygous point mutation (G32T) was identified in the bulge region of the IRE. CONCLUSION: The combination of early-onset cataracts and an elevated ferritin level should suggest this genetic syndrome.     

The contribution of the SPINK1 c.194 + 2T > C mutation to the clinical course of idiopathic chronic pancreatitis in Chinese patients

BackgroundRecent data suggest that the serine protease inhibitor Kazal type 1 (SPINK1) gene mutation is associated with idiopathic chronic pancreatitis. However, few studies have focused on the serine protease inhibitor Kazal type 1 c.194 + 2T > C mutation. Therefore, our goal was to study the prevalence and impact of serine protease inhibitor Kazal type 1 mutations on the clinical profile of idiopathic chronic pancreatitis patients in China.MethodsA retrospective-cohort study of 118 Chinese patients with idiopathic chronic pancreatitis was performed, and genetic tests were carried out to detect SPINK1 mutations. Subjects without pancreatitis were used as controls. In total, 118 idiopathic chronic pancreatitis patients and 100 control subjects were evaluated.ResultsThe serine protease inhibitor Kazal type 1 c.194 + 2T > C variant was present in 44.9% of patients with idiopathic chronic pancreatitis. The frequency of diabetes in idiopathic chronic pancreatitis patients with the serine protease inhibitor Kazal type 1 c.194 + 2T > C mutation (39.6%) was higher than that of patients without the mutation (9.2%). The time to occurrence of diabetes mellitus after idiopathic chronic pancreatitis symptom onset is significantly influenced by the c.194 + 2T > C mutation (p < 0.001). In addition, the mean age of diabetes onset in patients with the serine protease inhibitor Kazal type 1 c.194 + 2T > C mutation (38.33 ± 9.50) was significantly younger than that of patients without this mutation (49.67 ± 6.74).ConclusionsThe presence of the serine protease inhibitor Kazal type 1 c.194 + 2T > C mutation seems to be associated with idiopathic chronic pancreatitis and could predispose individuals to pancreatic diabetes onset at an earlier age.     

A novel mutation in RAB3GAP1 gene in Chinese patient causing the Warburg micro syndrome: A case report

Rationale:Warburg Micro syndrome is a rare, autosomal recessive disorder characterized by multiple organ abnormalities involving the ocular, nervous, and genital systems. This case report describes a novel mutation in the RAB3GAP1 gene associated with Warburg Micro syndrome.Patient concerns:A 6-month-old female infant with bilateral congenital cataracts and developmental delay was referred to our department for further assessment. She presented with facial dysmorphic features, including a prominent forehead, microphthalmia, wide nasal bridge, relatively narrow mouth, large anteverted ears, and micrognathia.Diagnoses:The patient was diagnosed with Warburg Micro syndrome based on clinical manifestations, as well as a novel homozygous mutation in RAB3GAP1: c.75–2A>C. Both parents were identified as heterozygotic carriers of this mutation.Interventions:Bilateral cataract extraction and anterior vitrectomy were performed at age 6 months, followed by physical rehabilitation. Convex lenses were used to protect the eyes postoperatively until intraocular lens implantation.Outcomes:Although the patient received physical rehabilitation, she suffered global developmental delay.Lessons:The c.75–2A>C mutation in RAB3GAP1 expands the spectrum of known mutations in this gene, and it may be associated with Warburg Micro syndrome. Genetic counselors may wish to take this finding into consideration, especially given the poor prognosis associated with the disease.     

A novel deletion of the L-ferritin iron-responsive element responsible for severe hereditary hyperferritinaemia-cataract syndrome

In the last few years, mutations that cause disease through increased efficiency of mRNA translation have been discovered. Hereditary hyperferritinaemia-cataract syndrome (HHCS) arises from various point mutations or deletions within the iron-responsive element (IRE) in the 5'-UTR of the L-ferritin mRNA. Each unique mutation confers a characteristic degree of hyperferritinaemia and severity of cataract in affected individuals. We report a novel six-nucleotide deletion identified in an Italian family presenting with elevated serum ferritin and early onset bilateral cataract. This deletion involves a sequence with a TCT repetition and may have occurred through a mechanism of slippage mispairing. Because of the above repetition, the observed mutation can be interpreted as deletion 22-27, 23-28, 24-29 or 25-30. Structural modelling predicted an IRE stem modification that is expected to markedly reduce the binding to iron-regulatory proteins. A double-gradient denaturing gradient gel electrophoresis (DG-DGGE) method easily detected the above deletion.     

Recurrent mutations in the iron regulatory element of L-ferritin in hereditary hyperferritinemia-cataract syndrome.

BACKGROUND AND OBJECTIVE: Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant disorder characterized by bilateral cataracts and increased serum and tissue L-ferritin, in the absence of iron overload. The deregulation of ferritin production is caused by heterogeneous mutations in the iron regulatory element (IRE) of L-ferritin that interfere with the binding of iron regulatory proteins. DESIGN AND METHODS: We have identified several patients from three unrelated Italian families with HHCS. Iron parameters were assessed by standard methods. The IRE element of L-ferritin was amplified by PCR using appropriate primers and directly sequenced. RESULTS: Ferritin levels ranged from 918 microg/L to 2490 microg/L in the patients studied. In one family bilateral cataracts were diagnosed early in life, whereas in the others cataracts were diagnosed around 40-50 years. The female proband of family 3 presented with a severe iron deficiency anemia, which was unrecognized because of the increased ferritin values. Sequencing of the IRE element of L-ferritin in the probands of the three families identified three different nucleotide substitutions (+32 GAE A, +40 AAE G and +39 CT) in the IRE of L-ferritin. These mutations have already been reported in unrelated subjects of different ethnic origins. INTERPRETATION AND CONCLUSIONS: Our findings are consistent with recurrent mutations associated with HHCS and underline the importance of this syndrome in the differential diagnosis of unexplained hyperferritinemia. In addition, the findings highlight the role played by transferrin saturation in the diagnosis of iron deficiency in these patients.     

Hereditary hyperferritinemia-cataract syndrome (HHCS) presenting with iron deficiency anemia associated with a new mutation in the iron responsive element of the L ferritin gene in a Swiss family

Hereditary hyperferritinemia-cataract syndrome (HHCS) is one of the differential diagnoses of hyperferritinemia (HF) with low or normal transferrin saturation but is usually not associated with anemia. Here, we report a case of a microcytic, hypochromic anemia with hyperferritinemia as the initial presentation of a combination of iron deficiency anemia and HHCS. The latter is an autosomal dominant disorder characterized by distinctive cataracts and HF in the absence of iron overload. Sequencing studies were carried out to look for mutations in the iron responsive element (IRE) of the L ferritin gene. A heterozygous single point mutation for a +24T to C substitution in the IRE of the L ferritin gene (=HGVS c.-176T>C) was detected which has not been described before. To evaluate the pathogenetic relevance of this new mutation, we performed family studies of parents and siblings. We could identify the father and one brother with HF, cataract, and the heterozygous +24T>C mutation. Neither the mother nor the five other siblings had HF, cataract or that mutation. We therefore conclude that this newly described heterozygous +24T>C mutation in the IRE of the L ferritin gene causes HHCS.     

A novel PMP22 insertion mutation causing Charcot–Marie–Tooth disease type 3: A case report

Rationale:Charcot–Marie–Tooth disease (CMT) is a group of hereditary neuropathies with clinical features of muscle atrophy, sensory loss, and foot deformities. CMT is related to a number of genes, such as peripheral myelin protein 22 gene (PMP22). Missense mutations, small deletion mutations, and duplications of PMP22 are common in CMT patients, but few insertion mutation cases of PMP22 have been reported.Patient concerns:A 26-year-old male patient with the complaint of general weakness, peroneal atrophy, and deformities in the extremities visited our hospital. The patient was born with bilateral thumbs and feet dystonia. Additionally, delayed feet arch development and delayed walking was observed when he was a child.Diagnosis:Using whole-exome sequencing and electrophysiological test, we identified a novel insertion mutation of PMP22 ({"type":"entrez-nucleotide","attrs":{"text":"NM_153322","term_id":"1674986609"}}NM_153322, c.54_55insGTGCTG, p.(L19delinsVLL)) in a 26-year-old male patient with peroneal atrophy and nerve conduction was not elicited in electromyography (EMG) study. The Protein Variation Effect Analyzer (PROVEAN) program analysis predicted that the variant is likely to be “deleterious.” SWISS-MODEL program predicted that alpha helix in original location was disrupted by inserted 6 bases, which may account for the occurrence of CMT3.Interventions:The patient received symptomatic and supportive treatments, and routine rehabilitation exercises during hospitalization.Outcomes:The condition of the patient was improved, but the disease could not be cured. At 1- and 3-months follow-up, manifestations of the patient were unchanged, and he could take care of himself.Lessons:Our findings link a novel PMP22 mutation with a clinical diagnosis of CMT3. The link between gene variation and CMT phenotype may help to reveal the structure and function of PMP22 protein and the pathogenesis of CMT. This study adds further support to the heterogeneity of PMP22 related CMT and provides solid functional evidence for the pathogenicity of the p.(L19delinsVLL) PMP22 variant. Moreover, with the development of high-throughput sequencing technology, the combination of next-generation sequencing (NGS) and conventional Sanger sequencing is becoming one of the comprehensive, inexpensive, and convenient tools for genetic diagnosis of CMT.     

Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A

OBJECTIVE: To investigate the levels of the pro-inflammatory cytokines IL-6, TNF-alpha, IL-1beta, IL-8, IL-10 and IL-12p70 in the plasma of patients with TNF receptor-associated periodic syndrome (TRAPS) in relation to CRP levels and treatment with etanercept. METHODS: Cytokine concentrations were measured in sequential plasma samples obtained from eight patients with a C33Y mutation in TNFRSF1A and diagnosed with TRAPS, using cytokine bead array. The TRAPS samples were compared with samples from normal controls and rheumatoid arthritis patients. RESULTS: Levels of IL-6 were significantly elevated in C33Y TRAPS patients and these correlated with CRP levels in some of the patients. IL-8 levels were also significantly elevated in the TRAPS patients. However, neither TNF-alpha nor IL-1beta demonstrated a similar increase. This differed from the patients with rheumatoid arthritis, for whom levels of IL-6, IL-8, TNF-alpha, IL-1beta and IL-10 were significantly elevated. The levels of detectable TNF-alpha in the TRAPS patients' plasma were elevated during etanercept treatment. CONCLUSIONS: The cytokine profile of C33Y TRAPS differs from that of a typical autoimmune inflammatory condition such as rheumatoid arthritis, as only IL-6 and IL-8 were elevated in C33Y TRAPS patients, as distinct from a generalized elevation of pro-inflammatory cytokines. However, only some of the C33Y patients tested showed a relationship between elevated IL-6 and CRP. This is consistent with clinical observations that there is marked heterogeneity between individuals with TRAPS, including those in the same family cohort. Although etanercept has a therapeutic effect in some TRAPS patients, it induces increased plasma concentrations of TNF-alpha, possibly by increasing TNF-alpha stability.     

Acute intestinal pseudo-obstruction (Ogilvie's syndrome): A case report

Acute colonic pseudo-obstruction, also known as Ogilvie's syndrome, is an acute clinical condition with clinical and radiological features of an acute large bowel obstruction in the absence of any mechanical cause. Patients presenting with Ogilvie's syndrome usually have underlying medical and surgical conditions predisposing them to the syndrome. In this article, we describe an elderly patient who presented with acute colonic pseudo-obstruction without any apparent cause.     

Two new class III G6PD variants [G6PD Tunis (c.920A > C: p.307Gln > Pro) and G6PD Nefza (c.968T > C: p.323 Leu > Pro)] and overview of the spectrum of mutations in Tunisia

We screened 423 patients referred to our laboratory after hemolysis triggered by fava beans ingestion, neonatal jaundice or drug hemolysis. Others were asymptomatic but belonged to a family with a history of G6PD deficiency. The determination of enzymatic activity using spectrophotometric method, revealed 293 deficient (143 males and 150 females). The molecular analysis was performed by a combination of PCR-RFLP and DNA sequencing to characterize the mutations causing G6PD deficiency. 14 different genotypes have been identified : G6PD A^? (376A > G;202G > A) (46.07%) and G6PD Med (33.10%) were the most common variants followed by G6PD Santamaria (5.80%), G6PD Kaiping (3.75%), the association [c.1311T and IVS11 93c] (3.75%), G6PD Chatham (2.04%), G6PD Aures (1.70%), G6PD A^? Betica (0.68%), the association [ 376G;c.1311T;IVS11 93c] (0.68%), G6PD Malaga, G6PD Canton and G6PD Abeno respectively (0.34%). Two novel missense mutations were identified (c.920A > C: p.307Gln > Pro and c.968T > C: p.323 Leu > Pro). We designated these two class III variants as G6PD Tunis and G6PD Nefza. A mechanism which could account for the defective activity is discussed.     

Haematological manifestations of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: A case report

Arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC) syndrome is a rare, fatal, multisystem disorder. Bleeding problems, which occur spontaneously and post organ biopsies, have been reported in these patients. We report the case of an infant who had life-threatening spontaneous nasal bleeding. A detailed assessment of her platelet function and morphology is presented.