A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia

Lichtenstein, Daniel A.; Crispin, Andrew; Sendamarai, Anoop K.; Campagna, Dean R.; Schmitz-Abe, Klaus; Sousa, Cristovão M.; Kafina, Martin D.; Schmidt, Paul; Niemeyer, Charlotte M.; Porter, John B.; May, Alison; Patnaik, Mrinal M.; Heeney, Matthew M.; Kimmelman, Alec C.; Bottomley, Sylvia S.; Paw, Barry H.; Markianos, Kyriacos; Fleming, Mark D.

doi:10.1182/blood-2016-05-719062

Cited by 37 publications

(35 citation statements)

References 13 publications

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“…Thanks to next generation sequencing (NGS) and whole exome sequencing (WES), new genes involved in CSA have been identified. The NDUFB11 anaemia is a moderate to severe normocytic anaemia that may be associated with mild myopathy (Lichtenstein et al , ). MT‐ATP6 anaemia is highly variable and could be associated with different comorbidities, varying from mild lactic acidosis and learning disabilities, mitochondrial encephalopathy, myopathy cardiomyopathy to severe metabolic compromise (Berhe et al , ).…”

Section: Introductionmentioning

confidence: 99%

Genotype/phenotype correlations of childhood‐onset congenital sideroblastic anaemia in a European cohort

et al. 2019

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Congenital sideroblastic anaemia (CSA) is a rare disease caused by germline mutations of genes involved in haem and iron-sulphur cluster formation, and mitochondrial protein biosynthesis. We performed a retrospective multicentre European study of a cohort of childhood-onset CSA patients to explore genotype/phenotype correlations. We studied 23 females and 20 males with symptoms of CSA. Among the patients, the most frequently mutated genes were ALAS2 (n = 10; 23Á3%) and SLC25A38 (n = 8; 18Á6%), causing isolated forms of microcytic anaemia of varying severity. Five patients with SLC19A2 mutations suffered from thiamine-responsive megaloblastic anaemia and three exhibited the 'anaemia, deafness and diabetes' triad. Three patients with TRNT1 mutations exhibited severe early onset microcytic anaemia associated with thrombocytosis, and two exhibited Bcell immunodeficiency, inflammatory syndrome and psychomotor delay. The prognoses of patients with TRNT1 and SLC2A38 mutations were generally dismal because of comorbidities or severe iron overload. No molecular diagnosis could be established in 14/43 cases. This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines.

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Section: Introductionmentioning

confidence: 99%

Genotype/phenotype correlations of childhood‐onset congenital sideroblastic anaemia in a European cohort

et al. 2019

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“…Somatic mutations in SF3B1 are found in ≥80% of patients, sometimes in combination with mutations in other genes, including JAK2V617F, ASXL1, DNMT3A, SETBP1 , and TET2 . Congenital SA is associated with mutations in nuclear genes involved in heme biosynthesis ( ALAS2 and SLC25A38 ), iron‐sulfur‐cluster biogenesis/transport ( ABCB7 and GLRX5 ), thiamine‐transport protein ( SLC19A1 ), structural subunits of the respiratory chain complex ( NDUFB11 ), and mitochondrial protein synthesis and chaperones ( PUS1, YARS2, LARS2 , and HSPA9 ) or with mutations in mitochondrial DNA ( MTATP6 , or large mtDNA deletions) involved in mitochondrial biogenesis …”

Section: Introductionmentioning

confidence: 99%

“…2,3 Congenital SA is associated with mutations in nuclear genes involved in heme biosynthesis (ALAS2 and SLC25A38), iron-sulfurcluster biogenesis/transport (ABCB7 and GLRX5), thiamine-transport protein (SLC19A1), structural subunits of the respiratory chain complex (NDUFB11), and mitochondrial protein synthesis and chaperones (PUS1, YARS2, LARS2, and HSPA9) or with mutations in mitochondrial DNA (MTATP6, or large mtDNA deletions) involved in mitochondrial biogenesis. [4][5][6][7][8][9][10][11] Although the association between hematological pathology and mitochondrial disorders is generally accepted, collaboration between hematologists and mitochondrial researchers is not common.…”

Section: Introductionmentioning

confidence: 99%

Sideroblastic anemia associated with multisystem mitochondrial disorders

Tesařová

Vondráčková

Stufkova

et al. 2018

Pediatric Blood & Cancer

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Background Sideroblastic anemia represents a heterogeneous group of inherited or acquired diseases with disrupted erythroblast iron utilization, ineffective erythropoiesis, and variable systemic iron overload. In a cohort of 421 patients with multisystem mitochondrial diseases, refractory anemia was found in 8 children. Results Five children had sideroblastic anemia with increased numbers of ring sideroblasts >15%. Two of the children had a fatal course of MLASA1 syndrome (mitochondrial myopathy, lactic acidosis, and sideroblastic anemia [SA]) due to a homozygous, 6‐kb deletion in the PUS1 gene, part of the six‐member family of pseudouridine synthases (pseudouridylases). Large homozygous deletions represent a novel cause of presumed PUS1‐loss‐of‐function phenotype. The other three children with SA had Pearson syndrome (PS) due to mtDNA deletions of 4 to 8 kb; two of these children showed early onset of PS and died due to repeated sepsis; the other child had later onset of PS and survived as the hematological parameters normalized and the disease transitioned to Kearns–Sayre syndrome. In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor. Conclusions Sideroblastic anemia was found in fewer than 1.2% of patients with multisystem mitochondrial disease, and it was usually associated with an unfavorable prognosis.

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“…Deletions, rearrangements, or duplications of mitochondrial DNA also induce the rare syndromic disorder with SA, known as PMPS, which is accompanied with metabolic acidosis and endocrine pancreatic insufficiency [33]. Recently, mutations in NADH:ubiquinone oxidoreductase subunit B11 (NDUFB11) [34], HSPA9 [the mitochondrial heat-shock protein family A (Hsp70) member 9] [35], and TRNT1 (tRNA nucleotidyl transferase 1) in SIFD (congenital SA associated with B-cell immunodeficiency, periodic fevers, and developmental delay) [36] have been identified to cause SAs in this category as well.…”

Section: Pathophysiology Of Ring Sideroblastsmentioning

confidence: 99%

Splicing factor mutations in MDS RARS and MDS/MPN-RS-T

Yoshimi

Abdel‐Wahab

2017

Int J Hematol

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A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia

Abstract: Key Points A recurring mutation in NDUFB11 causes congenital sideroblastic anemia. The NDUFB11 p.93del mutation impairs erythroid proliferation, but not differentiation.

Cited by 37 publications

References 13 publications

Genotype/phenotype correlations of childhood‐onset congenital sideroblastic anaemia in a European cohort

Genotype/phenotype correlations of childhood‐onset congenital sideroblastic anaemia in a European cohort

Sideroblastic anemia associated with multisystem mitochondrial disorders

Splicing factor mutations in MDS RARS and MDS/MPN-RS-T

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