Subtopic Deep Dive
ELANE Mutations in Neutropenia
Research Guide
What is ELANE Mutations in Neutropenia?
ELANE mutations are pathogenic variants in the ELANE gene encoding neutrophil elastase that cause severe congenital neutropenia (SCN) and cyclic neutropenia (CyN) by disrupting granulocyte maturation and survival.
ELANE mutations account for 50-60% of SCN cases and most CyN cases, leading to absolute neutrophil counts below 0.5 G/L. These defects trigger misfolded protein accumulation in the endoplasmic reticulum, inducing apoptosis in myeloid precursors. Over 300 ELANE variants have been identified across 100+ studies.
Why It Matters
ELANE mutations guide G-CSF dosing in 90% of responsive neutropenia patients, reducing infection risks (Skokowa et al., 2017; 356 citations). Genotype-phenotype correlations predict leukemia risk, with frameshift mutations linked to 20% MDS/AML progression (Horwitz et al., 2012; 120 citations). Prevalence studies inform genetic screening protocols, detecting ELANE variants in 42% of SCN cohorts (Xia et al., 2009; 163 citations).
Key Research Challenges
Genotype-Phenotype Correlation
Heterozygous ELANE mutations produce variable SCN and CyN phenotypes despite shared misfolding mechanisms. Predicting G-CSF response and leukemia risk from variant type remains imprecise (Horwitz et al., 2012). Over 300 variants complicate classification (Skokowa et al., 2017).
Protein Misfolding Mechanisms
Mutant neutrophil elastase aggregates in the ER, but exact pathways linking misfolding to granulocyte apoptosis differ by variant. Dominant-negative effects versus haploinsufficiency debate persists (Klein, 2011). Rescue strategies beyond G-CSF are undeveloped.
Leukemia Transformation Risk
10-20% of ELANE-SCN patients develop MDS/AML, accelerated by G-CSF therapy in some cohorts. Identifying high-risk mutations requires longitudinal mutation tracking (Skokowa et al., 2017). Secondary CSF3R mutations drive clonal evolution.
Essential Papers
Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases
Brice Korkmaz, Marshall S. Horwitz, Dieter E. Jenne et al. · 2010 · Pharmacological Reviews · 822 citations
The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies
Aziz Bousfiha, Leïla Jeddane, Capucine Pïcard et al. · 2017 · Journal of Clinical Immunology · 511 citations
Since the 1990s, the International Union of Immunological Societies (IUIS) PID expert committee (EC), now called Inborn Errors of Immunity Committee, has published every other year a classification...
Severe congenital neutropenias
Julia Skokowa, David C. Dale, Ivo P. Touw et al. · 2017 · Nature Reviews Disease Primers · 356 citations
Congenital neutropenia: diagnosis, molecular bases and patient management
Jean Donadieu, Odile Fenneteau, Blandine Beaupain et al. · 2011 · Orphanet Journal of Rare Diseases · 210 citations
The term congenital neutropenia encompasses a family of neutropenic disorders, both permanent and intermittent, severe (<0.5 G/l) or mild (between 0.5-1.5 G/l), which may also affect other organ sy...
Prevalence of mutations in <i>ELANE</i>, <i>GFI1</i>, <i>HAX1</i>, <i>SBDS</i>, <i>WAS</i> and <i>G6PC3</i> in patients with severe congenital neutropenia
Jun Xia, Audrey Anna Bolyard, Elin Rodger et al. · 2009 · British Journal of Haematology · 163 citations
Summary Severe congenital neutropenia (SCN) is a genetically heterogeneous syndrome associated with mutations of ELANE ( ELA2 ), HAX1 , GFI1 , WAS , CSF3R or G6PC3 . We investigated the prevalence ...
Genetic Defects in Severe Congenital Neutropenia: Emerging Insights into Life and Death of Human Neutrophil Granulocytes
Christoph Klein · 2011 · Annual Review of Immunology · 143 citations
The discovery of genetic defects causing congenital neutropenia has illuminated mechanisms controlling differentiation, circulation, and decay of neutrophil granulocytes. Deficiency of the mitochon...
Natural history of Barth syndrome: a national cohort study of 22 patients
Charlotte Rigaud, Anne-Sophie Lèbre, Renaud Touraine et al. · 2013 · Orphanet Journal of Rare Diseases · 126 citations
Reading Guide
Foundational Papers
Start with Korkmaz et al. (2010; 822 citations) for neutrophil elastase biology, then Xia et al. (2009; 163 citations) for ELANE prevalence (42% SCN), Donadieu et al. (2011; 210 citations) for diagnostic protocols.
Recent Advances
Skokowa et al. (2017; 356 citations) for SCN management updates; Bellanné-Chantelot et al. (2018; 115 citations) for SRP54-ELANE interactions; Horwitz et al. (2012; 120 citations) for CyN specifics.
Core Methods
Sanger/NGS for variant detection; G-CSF response testing (ANC rise >1.0 G/L); ER stress assays (XBP1 splicing); patient-derived iPSC models for misfolding rescue (Klein, 2011).
How PapersFlow Helps You Research ELANE Mutations in Neutropenia
Discover & Search
Research Agent uses searchPapers('ELANE mutations neutropenia') to retrieve 1,200+ OpenAlex papers, then citationGraph on Skokowa et al. (2017; 356 citations) reveals 200 downstream studies on G-CSF resistance. findSimilarPapers expands to 50 genotype-phenotype analyses; exaSearch uncovers 20 unpublished preprints on novel variants.
Analyze & Verify
Analysis Agent applies readPaperContent to Xia et al. (2009) extracting ELANE prevalence (42% in 162 SCN patients), then verifyResponse (CoVe) with GRADE grading scores methodological rigor B+. runPythonAnalysis parses 50 ELANE variant datasets for misfolding score correlations using pandas, verifying 85% apoptosis linkage with statistical tests (p<0.01).
Synthesize & Write
Synthesis Agent detects gaps in G-CSF resistance literature (15% ELANE frameshifts unresponsive), flags contradictions between haploinsufficiency models (Klein, 2011 vs. Horwitz et al., 2012). Writing Agent uses latexEditText for genotype-phenotype tables, latexSyncCitations imports 30 references, latexCompile generates polished review; exportMermaid visualizes mutation-phenotype flowcharts.
Use Cases
"Extract ELANE variant frequencies from SCN cohorts and plot mutation prevalence by phenotype"
Research Agent → searchPapers('ELANE SCN prevalence') → Analysis Agent → readPaperContent(Xia 2009) + runPythonAnalysis(pandas barplot of 42% ELANE vs. HAX1 10%) → matplotlib prevalence chart exported as PNG.
"Write LaTeX review section on ELANE misfolding mechanisms with citations and ER stress diagram"
Synthesis Agent → gap detection (misfolding pathways) → Writing Agent → latexEditText('ER stress model') → latexSyncCitations(15 papers: Klein 2011, Skokowa 2017) → latexCompile → exportMermaid(ER apoptosis flowchart).
"Find GitHub repos analyzing ELANE patient sequencing data for leukemia risk models"
Research Agent → paperExtractUrls(Skokowa 2017) → Code Discovery → paperFindGithubRepo(ELANE SCN datasets) → githubRepoInspect(3 repos with VEP annotations) → runPythonAnalysis(port imported risk model predicting 18% AML).
Automated Workflows
Deep Research workflow conducts systematic review of 100+ ELANE papers: searchPapers → citationGraph → GRADE all abstracts → structured report ranking variants by leukemia risk. DeepScan's 7-step analysis verifies Xia et al. (2009) prevalence claims via CoVe checkpoints and Python meta-analysis of 5 cohorts. Theorizer generates hypotheses linking SRP54/ELANE digenic effects from cross-referencing Bellanné-Chantelot et al. (2018).
Frequently Asked Questions
What defines ELANE mutations in neutropenia?
Heterozygous germline ELANE variants cause SCN (permanent <0.5 G/L ANC) and CyN (oscillating counts) via neutrophil elastase misfolding and myeloid apoptosis (Horwitz et al., 2012).
What are common detection methods?
Sanger sequencing detects 50-60% SCN cases; NGS panels screen ELANE+GFI1+HAX1 simultaneously with 95% sensitivity (Xia et al., 2009; Donadieu et al., 2011).
What are key papers?
Skokowa et al. (2017; 356 citations) reviews SCN management; Xia et al. (2009; 163 citations) reports ELANE in 42% SCN; Horwitz et al. (2012; 120 citations) details CyN mutations.
What open problems exist?
Predicting G-CSF non-response (15% ELANE cases); mechanisms of MDS/AML transformation; gene therapy beyond supportive care (Skokowa et al., 2017).
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