A Case of Hereditary Spherocytosis Caused by a Novel Homozygous Mutation in the SPTB Gene Misdiagnosed as β-Thalassemia Intermedia Due to a KLF1 Gene Mutation

The aim of the paper is to determine the impact of COL1A1 gene polymorphism on soft tissue injuries in maternity patients. Materials and Methods. The study involved 62 maternity patients who were divided into 2 groups. The first group included 45 patients (72.5 %) without type 1 collagen mutation, alpha 1 Sp1-polymorphism (G2046T) G/G. The second group consisted of 16 patients (27.5 %) with mutation in COL1A1 gene, Sp1-polymorphism (G2046T) G/T. During the study, a homozygous mutation, Sp1-polymorphism (G2046T) T/T was observed in one patient. Age, parity and mean fetal weight of women were comparable. Results. In patients with the COL1A1 mutation, Sp1-polymorphism (G2046T), the incidence of soft tissue birth injuries was 2.3 times higher than in those without such a mutation. Thus, it was confirmed that COL1A1 gene mutation contributes to the soft tissue trauma of the birth canal. It can be regarded as a prognostic criterion and as a basis for preventive measures during pregnancy. Conclusion. Birth trauma risks remain a controversial issue. One of the factors may be COL1A1 gene mutation. Key words: birth trauma, pelvic floor muscle insufficiency, collagen 1 gene polymorphism (COL1A1). Цель работы – определить роль полиморфизма гена COL1A1 у женщин с родовыми травмами мягких тканей родовых путей. Материалы и методы. В исследовании приняло участие 62 родильницы, которые были разделены на 2 группы. В первую группу включены 45 (72,5 %) родильниц, у которых мутация коллагена типа 1, альфа 1 Sp1-polymorphism (G2046T) G/G не обнаружена. Во второй группе, состоящей из 16 (27,5 %) родильниц, обнаружена мутация гена COL1A1 Sp1-polymorphism (G2046T) G/T. В процессе проведения исследования у одной пациентки обнаружена гомозиготная мутация Sp1-polymorphism (G2046T) T/T. Пациентки были сопоставимы по возрасту, паритету и средней массе плода. Результаты. У пациенток с мутацией COL1A1 Sp1-polymorphism (G2046T) частота родовых травм мягких тканей оказалась в 2,3 раза выше, чем у пациенток без мутации. Таким образом, подтверждено, что мутация данного гена имеет определенное значение в реализации риска травм мягких тканей родовых путей, что может послужить прогностическим критерием и основанием для проведения профилактических мероприятий в период беременности. Выводы. Вопрос о рисках родового травматизма остается спорным. Одним их факторов может явиться мутация гена COL1A1. Ключевые слова: родовой травматизм, недостаточность мышц тазового дна, полиморфизм гена коллагена 1 (COL1A1).

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BETA-GLOBIN GENE MUTATIONS IN TURKISH CHILDREN WITH BETA-THALASSEMIA: RESULTS FROM A SINGLE CENTER STUDY

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2013.055 ◽

2013 ◽

Vol 5 (1) ◽

pp. e2013055 ◽

Cited By ~ 13

Author(s):

Ali Fettah ◽

Cengiz Bayram ◽

Nese Yarali ◽

Pamir Isik ◽

Abdurrahman Kara ◽

...

Keyword(s):

Globin Gene ◽

Gene Mutations ◽

Thalassemia Major ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Thalassemia Intermedia ◽

Turkish Children ◽

Tertiary Center

Introduction: The beta thalassemias are common genetic disorders in Turkey and in this retrospective study our aim was to evaluate β-globin chain mutations and the phenotypic severity of β-thalassemia patients followed-up in our hospital, a tertiary center which serves patients from all regions of Turkey. Materials and Methods: 106 pediatric patients were analysed for β-globin gene mutations by using DNA analysis. Patients were classified as having β-thalassemia major or β-thalassemia intermedia based on age at diagnosis, transfusion frequency and lowest hemoglobin concentration in between transfusions. Results: There were 106 patients (52.8% female and 47.2% male) with a mean age of 11.2±5 years (1.6 – 22.3 years). Eighty-four (79.2%) patients had β-thalassemia major, whereas the remaining 22 patients (20.8%) were identified as having β-thalassemia intermedia. Overall, 18 different mutations were detected on 212 alleles. The most frequently encountered mutation was IVS I.110 (G>A) (35.3%), followed by Codon 8 del-AA (10.4%), IVS II.1 (G>A) (8%), IVS I.1 (G>A) (7.5%), Codon 39 (C>T) (7.1%) and Codon 5 (-CT) (6.6%), which made up 79.4% of observed mutations. According to present results, IVS I.110 (G>AA) was the most frequent mutation observed in this study, as in other results from Turkey. Evaluation of β-thalassemia mutations in 106 patients with 212 alleles, revealed the presence of homozygous mutation in 85 patients (80.2%) and compound heterozygous mutation in 21 patients (19.8%). The mutations detected in patients with homozygous mutation were IVS I.110 (G>A) (38.8%), Codon 8 del –AA (11.8%), IVS II.1 (G>A) (8.2%) and IVS I.1 (G>A) (8.2%). Observed mutations in the compound heterozygotes were Codon 39 (C>T)/Codon 41-42 (-CTTT) (14.3%), IVS I.110 (G>A)/Codon 39(C>T) (14.3%), IVS I.110 (G>A)/Codon 44(-C) (14.3%), and IVS II.745 (C>G)/ 5’UTR + 22 (G>A) (9.5%). Conclusion: Our hospital is a tertiary referral center that provides care to patients from all over the country, and thus the distribution of mutations observed in the current study is significant in term of representing that of the country as a whole.

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Delayed fetal hemoglobin switching in subjects with KLF1 gene mutation

Blood Cells Molecules and Diseases ◽

10.1016/j.bcmd.2011.10.003 ◽

2012 ◽

Vol 48 (1) ◽

pp. 22-24 ◽

Cited By ~ 16

Author(s):

Stefania Satta ◽

Lucia Perseu ◽

Liliana Maccioni ◽

Nicolina Giagu ◽

Renzo Galanello

Keyword(s):

Gene Mutation ◽

Fetal Hemoglobin ◽

Hemoglobin Switching ◽

Klf1 Gene

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Hereditary Spherocytosis

Blood ◽

10.1182/blood.v6.11.1073.1073 ◽

1951 ◽

Vol 6 (11) ◽

pp. 1073-1098 ◽

Cited By ~ 60

Author(s):

LAWRENCE E. YOUNG ◽

MARY JANE IZZO ◽

RICHARD F. PLATZER

Keyword(s):

Body Temperature ◽

Gene Mutation ◽

Hereditary Spherocytosis ◽

Osmotic Fragility ◽

Red Cells ◽

Laboratory Findings ◽

Low Degree ◽

Qualitative Test ◽

Chronic Hemolytic Anemia

Abstract Clinical, hematologic and genetic data on 28 cases of hereditary spherocytosis are presented for the purpose of characterizing this disorder as completely as possible. On the basis of this experience it is recommended that the following typical laboratory findings be sought in establishing a diagnosis in suspected cases: (1) Presence of spherocytes or abnormally thick red cells in peripheral blood; (2) greater than normal osmotic fragility of the red cells; in cases in which the fragility of fresh cells is not significantly increased, determinations should be made after sterile incubation of the blood at body temperature for 24 hours; (3) greater than normal mechanical fragility of freshly drawn red cells; (4) negative antiglobulin (Coombs) test; (5) greater than normal lysis of the red cells during sterile incubation at body temperature for 48 hours; and (6) presence of similar abnormalities in relatives. Abnormality of the erythrocyte persisted in all of the 11 patients in this series followed one or more years after splenectomy. An unusual case of chronic hemolytic anemia is described but not included in the numbered series because (1) both parents were hematologically normal and (2) spherocytosis and abnormally great osmotic and mechanical fragility and autohemolysis could not be demonstrated after the fifth postoperative month. Classification of this case is deferred pending further experience. Demonstration in a parent, sibling or offspring of red cells showing the afore-mentioned abnormalities is necessary for an unequivocal diagnosis, but this requirement cannot always be met because relatives may not be available for examination. Moreover, when parents and/or several siblings are examined without positive findings, low gene expressivity, gene mutation and illegitimacy may be considered as explanations. Evidence is cited to suggest the possibility of a low degree of penetrance or expression in some cases and to illustrate the need for still more sensitive laboratory tests that might aid in diagnosis of the mildest forms of this disease. The lower incidence of spherocytosis in siblings of propositi than in offspring of propositi is cited as evidence bearing on the theory of gene mutation in some propositi. A simplified "qualitative" test of osmotic fragility of incubated red cells is described.

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New macular findings in individuals with biallelic KLHL7 gene mutation

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2018-000234 ◽

2019 ◽

Vol 4 (1) ◽

pp. e000234 ◽

Cited By ~ 2

Author(s):

Ling Zhi Heng ◽

Joanna Kennedy ◽

Sarah Smithson ◽

Ruth Newbury-Ecob ◽

Amanda Churchill

Keyword(s):

Young Adults ◽

Gene Mutation ◽

Late Onset ◽

Protein A ◽

Retinal Dystrophy ◽

Gene Mutations ◽

Photoreceptor Cells ◽

Ubiquitin Proteasome System ◽

Proper Function ◽

Homozygous Mutation

ObjectiveThe ubiquitin-proteasome system pathway has been recognised as a crucial cellular mechanism for the proper function of photoreceptor cells. In particular, ubiquitin ligases (E3s) recognise and ubiquitinate specific proteins for degradation. The KLHL7 protein (a BTB-Kelch protein) has been found to play an important role in this process. There have been several reports that heterozygous mutations in the KLHL7 gene in adults are responsible for a rare cause of late-onset autosomal dominant retinitis pigmentosa with preservation of central vision and homozygous mutations in two young children, with Crisponi syndrome (CS)/cold-induced sweating syndrome type 1, result in a recessive form of early-onset peripheral retinal dystrophy type changes. The majority of children do not survive through to adulthood. The objective of this study is to report the visual symptoms and signs of two young adults clinically diagnosed with overlapping BOS/Cisproni syndrome, expanding the phenotypic presentation of KLHL7 gene mutations.Methods and analysisThis is a case report of the ophthalmic findings of two siblings with biallelic KLHL7 gene mutations. Siblings born to a non-consanguineous family and diagnosed with the overlapping clinical phenotype of Bohring-Opitz and and confirmed biallelic KLHL 7 gene mutation by whole exome sequencing were identified. Ophthlamic history and fundal examination was performed and analysed.ResultsBoth patients had similar retinal findings. The fundus shows confluent hypopigmented/pale yellow lesions in the mid-periphery. The optic disc appears to be pale with a ring of atrophy and vessels appear attenuated. The macular of the younger patient shows a depigmented area around the fovea giving a bull’s-eye appearance while the older sibling shows a fibrotic ring around the fovea suggesting a more advanced pathology.ConclusionThis paper expands the retinal phenotype to include a distinctive maculopathy in a recently described homozygous mutation in the KLHL7 gene in two young adults presenting with features that overlap the Bohring-Opitz syndrome and CS.

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Novel genotyping assay for the nt230 (del4) ABCB1 gene mutation and its allele frequency in Border Collie dogs in Mexico

Journal of Veterinary Diagnostic Investigation ◽

10.1177/10406387211033839 ◽

2021 ◽

pp. 104063872110338

Author(s):

Jorge Galindo ◽

Miguel A. Ayala ◽

David R. Sánchez ◽

Cecilia Hernández ◽

Theodor Duifhuis

Keyword(s):

Gene Mutation ◽

Restriction Analysis ◽

Small Subset ◽

Homozygous Mutation ◽

Wild Type ◽

Multidrug Resistance Gene ◽

Abcb1 Gene ◽

Western Mexico ◽

P Glycoprotein ◽

Genotype Frequencies

A 4-bp deletion in the ATP-binding cassette subfamily B member 1 ( ABCB1) gene, also referred to as the multidrug resistance gene ( MDR1), produces stop codons that cause premature termination of P-glycoprotein 1 (P-gp) synthesis. Dogs with the homozygous mutation do not express functional P-gp, which increases their sensitivity markedly to many common veterinary drugs. We detected the nt230 (del4) ABCB1 mutation in Border Collie dogs in western Mexico with a simple and affordable primer-introduced restriction analysis PCR (PIRA-PCR). PIRA-PCR clearly identified all genotypes in our sample of 104 dogs. Genotype frequencies were 0.952 (wild/wild), 0.029 (wild/mut) and 0.019 (mut/mut). Allele frequencies were 0.033 (mutant alleles) and 0.966 (wild-type alleles). In this small subset of the Mexican dog population, we found a higher prevalence of the nt230 (del4) MDR1/ABCB1 gene mutation than reported in other countries.

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Band 3 Courcouronne: Homozygous Mutation Ser667Phe Causes Severe Hereditary Spherocytosis and Incomplete Distal Renal Tubular Acidosis.

Blood ◽

10.1182/blood.v108.11.1563.1563 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1563-1563 ◽

Cited By ~ 1

Author(s):

Jean Delaunay ◽

Ashley Toye ◽

Rosalind Williamson ◽

Moudji Khanfar ◽

Brigitte Bader-Meunier ◽

...

Keyword(s):

Renal Tubular Acidosis ◽

Blood Cells ◽

Hereditary Spherocytosis ◽

Mdck Cells ◽

Band 3 ◽

Anion Transport ◽

Homozygous Mutation ◽

Kidney Cells ◽

Red Cell ◽

Renal Tubular

Abstract We describe the second case of a homozygous mutation in band 3 (anion exchanger 1 (AE1), SLC4A1) causing both hereditary spherocytosis (HS) and distal renal tubular acidosis (dRTA). This new variant differed from the previous homozygous variant (Band 3 Coimbra, Ribeiro et al, Blood2000: 96, 1602) in that a significant amount of band 3 was present in the red cell membrane and the dRTA was incomplete. In the proband, an Algerian male baby, a severe hemolytic anemia rapidly developed following birth. Low hemoglobin (3.5 g Hb/dL) at D12 demanded a first transfusion. Hepato-splenomegaly, marked palor and jaundice were noted. Eight transfusions were administered in the following months. Subtotal splenectomy, performed at the age of 9 months, cancelled the transfusional needs. Veinous blood examined after splenectomy showed band 3 to be reduced to ~35% of normal, as shown by immunoblotting. The other known proteins of the band 3/Rh macrocomplex were also found to be reduced. The parents were first cousins. Both showed mild spherocytosis associated with a mild band 3 deficiency. DNA sequence analysis revealed a novel homozygous mutation: TCC to TTC at codon 667 in exon 16, leading to an amino acid substitution: Ser667Phe, located in proposed transmembrane helix 8. Both parents were heterozygous for the same mutation. Anion transport (sulphate uptake) in the patient’s red cells was ~40% normal, showing that transport specific activity of the mutant band 3 was not affected. The mutant red cell band 3 and kidney band 3 were expressed in Xenopus oocytes, with and without co-expression of glycophorin A (GPA). There was very little chloride transport detected in oocytes expressing either mutant red cell or kidney protein alone, but transport was partially rescued by co-expression of GPA. After birth the child showed a temporary acidosis which spontaneously receded. No nephrocalcinosis has been noted to date. At 2 years of age, an ammonium chloride challenge suggested that the child has incomplete dRTA; over the seven hours of the test the blood bicarbonates decreased down to 15.6 mmoles/L, but urinary pH remained above 5.90. Stable expression of mutant kidney band 3 in non-polarised Madin-Darby canine kidney (MDCK) cells showed that the mutant protein was retained in the endoplasmic reticulum. We are currently investigating the effects of this mutant in polarized MDCK cells. Overall our results suggest that the Ser667Phe does not affect the anion transport function of band 3 but causes a trafficking defect in both red blood cells and kidney cells. The trafficking defect may be less severe in red blood cells where it is probably attenuated by the chaperone-like effect of GPA, which is not expressed in kidney cells. The fact that the hematological manifestations are far more conspicuous than their nephrologic counterpart will be discussed.

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