alexa Mutations in ELANE and COH1 (VPS13B) Genes Cause Severe Neutropenia in a Patient with Cohen Syndrome | Open Access Journals
ISSN: 2155-9899
Journal of Clinical & Cellular Immunology
Like us on:
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

Mutations in ELANE and COH1 (VPS13B) Genes Cause Severe Neutropenia in a Patient with Cohen Syndrome

Lauren Beene1,2, Baozhong Xin1, Claudia Lukas3 and Heng Wang1,2*
1DDC Clinic -- Center for Special Needs Children, Middlefield, Ohio, USA
2Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital, Cleveland, Ohio, USA
3Department of Hematology-Oncology, All Children’s Hospital, St. Petersburg, Florida, USA
Corresponding Author : Heng Wang, MD
PhD, DDC Clinic -- Center for Special Needs Children
14567 Madison Road, Middlefield
OH 44062, USA
Tel: 440-632-1668
Fax: 440-632-1697
E-mail: [email protected]
Received: October 27, 2015 Accepted: December 16, 2015 Published: December 28, 2015
Citation: Beene L, Xin B, Lukas C, Wang H (2015) Mutations in ELANE and COH1 (VPS13B) Genes Cause Severe Neutropenia in a Patient with Cohen Syndrome. J Clin Cell Immunol 6:378. doi:10.4172/2155-9899.1000378
Copyright: © 2015 Beene L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Related article at Pubmed, Scholar Google

Visit for more related articles at Journal of Clinical & Cellular Immunology

Abstract

In this case report we describe a patient with cohen syndrome and severe neutropenia. The patient was found to have a mutation of previously undetermined significance in the ELANE gene and compound heterozygous mutations in the COH1 gene causing Cohen syndrome. While the mutation in ELANE may not have led to clinically significant neutropenia independently, the presence of this mutation in conjunction with mutations in COH1 led to neutropenia that was more severe than what is typically seen in Cohen syndrome. This case report suggests that the combination of mutations in ELANE and COH1, both impacting similar intracellular trafficking mechanisms, led to an exaggerated clinical phenotype. Based on this case presentation, we encourage consideration of additional candidate genes when an identified genetic mutation cannot fully explain the scope or severity of the clinical picture, as recognition of all mutations impacting a clinical phenotype will help achieve a more comprehensive diagnosis.

Abstract

In this case report we describe a patient with cohen syndrome and severe neutropenia. The patient was found to have a mutation of previously undetermined significance in the ELANE gene and compound heterozygous mutations in the COH1 gene causing Cohen syndrome. While the mutation in ELANE may not have led to clinically significant neutropenia independently, the presence of this mutation in conjunction with mutations in COH1 led to neutropenia that was more severe than what is typically seen in Cohen syndrome. This case report suggests that the combination of mutations in ELANE and COH1, both impacting similar intracellular trafficking mechanisms, led to an exaggerated clinical phenotype. Based on this case presentation, we encourage consideration of additional candidate genes when an identified genetic mutation cannot fully explain the scope or severity of the clinical picture, as recognition of all mutations impacting a clinical phenotype will help achieve a more comprehensive diagnosis.

Keywords

ELANE; ELA2; COH1; Severe congenital neutropenia; Cohen syndrome; Synergistic effect

Introduction

Congenital neutropenia is characterized by chronic neutropenia presenting early in life and is attributed to numerous genetic causes, either isolated or as part of a syndrome [1]. The most common cause of isolated congenital neutropenia is ELANE-related severe congenital neutropenia (SCN) [2-4]. Additional cases of isolated congenital neutropenia have been attributed to mutations in other genes such as CSF3R, GFI1, WAS, and CXCR4 [1]. Congenital neutropenia is also a feature of numerous genetic syndromes, including Kostmann disease (HAX1), SCN type 4 (G6PC3), Hermansky-Pudlak syndrome type 2 (AP3B1), Cohen syndrome (CS, COH1), and others [1].

Neutropenia in ELANE-related SCN is characteristically severe (absolute neutrophil count [ANC] <500 cells/μl) and is associated with significant bacterial infections in childhood, and affected individuals almost universally require treatment with granulocyte colony stimulating factor (G-CSF) [1,4]. The neutropenia of CS is described as non-cyclic, mild-to-moderate (ANC usually ranging from 500-1200 cells/μl), and not typically requiring treatment with G-CSF [5-8]. The extra-hematopoietic features of CS are broad and include facial dysmorphism, microcephaly, developmental delay, hypotonia, joint hypermobility, retinal dystrophy, progressive high myopia, and truncal obesity (OMIM #216550) [8-12].

In this case report we describe a patient with severe neutropenia who was found to have mutations in both ELANE and COH1.

Case

A 14-year-old girl with complex medical history had been evaluated for severe chronic neutropenia over the course of four years. She was initially referred to hematology-oncology at age 10, and at that time her neutropenia was non-cyclical and ranged from mild-to-severe (ANC 200-1100 cells/μl). Her neutropenia continued to dip into the severe range, and at age 14 she experienced recurrent infections of Streptococcal pharyngitis, otitis media, and methicillin resistant Staphylococcus aureus skin lesions. She had a history of mouth ulcers and gingivitis, but no other significant infections.

Of note, the patient also had multiple congenital clinical findings including hypotonia, joint laxity, microcephaly, facial dysmorphism, myopia, and severe developmental delay. Previous evaluations to explain her neutropenia and syndromic features were unrevealing. There was no family history of clinically significant neutropenia or recurrent infections. There was no family history of consanguinity.

Physical exam was notable for microcephaly, short stature, and truncal obesity. Abnormal facial features included prominent eyebrows, prominent nasal tip, full lips with wide philtrum, and posteriorly rotated ears with simple helices. She had increased extensibility of the elbows and small joints, 2,3 toe syndactyly, and long and slender fingers and toes. She had one café-au-lait lesion on the abdomen.

Her neutropenia was then investigated more closely. Immunological causes of neutropenia were largely excluded. ANA and granulocyte antibody were negative. Immunoglobulins were within normal limits. Coombs test was weakly positive, which was suspected to be secondary to drug-effect as reticulocyte count was not elevated and she had no history of anemia. Her bone marrow biopsy was normal.

Genetic testing was performed for mutations in the ELANE gene. Results revealed a heterozygous c.770C>T variant in exon 5 of ELANE in the patient (Figure 1), resulting in replacement of a proline with a leucine residue at codon 257 of the ELANE protein (p.Pro257Leu). The patient’s father was heterozygous for this mutation, while he did not have a history of clinically significant neutropenia, he was later found to have borderline neutropenia with ANC 1400 cells/μl. The patient’s mother was wild type for this variant.

As the ELANE mutation alone could not explain her extra-hematopoietic features, a COH1 (VPS13B) gene test was also performed and revealed 2 heterozygous mutations, a deletion of 4 nucleotides in exon 11 leading to frameshift (c.1495_1498delTTTG, p.Phe499Ilefs*28), and a C to T nucleotide substitution in exon 14 leading to a stop codon (c.1915C>T, p.Arg639Ter) (Figure 1). While not previously reported, these mutations are predicted to result in truncated protein. Further, none of them has been observed in the 1000 Genomes Project or the NHLBI Exome Sequencing Project databases, indicating they are not common benign variants in the general population. Thus the detection of these two mutations was consistent with a diagnosis of CS. The patient’s father was found to be a carrier of the c.1915C>T mutation (Figure 1). The patient’s mother did not carry a COH1 mutation in her blood DNA, and thus the patient’s second mutation could be explained by maternal mosaicism or de novo mutation.

Over the next few months the patient’s ANC levels continued to decrease, with her lowest ANC 90 cells/μl. She was ultimately started on G-CSF with immediate improvement of her neutropenia.

Discussion

Here we describe the atypical presentation of severe neutropenia in a girl with Cohen syndrome who also harbors a mutation of previously undetermined significance in ELANE, the gene most often associated with SCN [3]. This case brings to light the potential role of synergy in genetic disorders, as well as the importance of considering a second mutation when clinical and laboratory features cannot be explained by mutation in a single gene.

In this patient case, a heterozygous missense mutation was identified in the carboxyl terminus of ELANE (Pro257Leu). Multiple mutations associated with SCN have been discovered in this region, however Pro257Leu was previously described as having undetermined significance [13-16]. Specifically, Germeshausen et al. detected Pro257Leu in 2% of individuals with SCN or cyclic neutropenia (CN) and in 1.2% of controls, and while this mutation was predicted to be deleterious, it was ultimately classified as a non-disease-causing low frequency polymorphism [15]. Similar variants of undetermined significance have also been found in nearby DNA regions such as Pro228Leu and Pro233Leu in individuals with SCN and CN [16,17].

Given these prior reports, as well as the status of the patient’s father as carrying the Pro257Leu mutation, this patient’s ELANE mutation could have been dismissed. However, we suspect the combination of mutations in ELANE and COH1, both impacting similar intracellular trafficking mechanisms, is what explains our patient’s exaggerated phenotype. Indeed, COH1 (or VPS13B; vacuolar protein sorting 13B) encodes a matrix protein required for maintained integrity of the peripheral Golgi membrane [18]. A recent study detected an abnormal glycosylation pattern in serum proteins of individuals with CS, and found early endosomes to be nearly absent in CS fibroblasts [19]. These findings, along with the known role of its Saccharomyces cerevisiae homologue VPS13B in trafficking of membrane proteins from the trans-Golgi network to the prevacuolar compartment, suggest COH1 plays a role in endosomal-lysosomal trafficking [11].

Mutations in ELANE may lead to dysfunctional intracellular trafficking of the protein it encodes, neutrophil elastase [1,13,20-22]. Upon exposure to inflammatory stimuli, bactericidal neutrophil elastase is released to the extracellular environment [1,20]. It is suspected that mutated ELANE is not properly shuttled to azurophilic granules, and is instead sent in excess to the plasma membrane where it causes damage [21,22]. This theory is strengthened by the finding that mutated ELANE has impaired binding to AP3, an adaptor protein that shuttles cargo proteins from the trans-Golgi network to lysosomes [21,23]. Mutations in AP3 causes canine CN and Hermansky-Pudlak syndrome type 2, a genetic disorder of humans associated with neutropenia and partial albinism [14,21].

While SCN is traditionally considered a monogenetic disorder, the current case presentation adds support for the potential of more than one mutation to impact the phenotype of inherited neutropenia. Previous studies have also presented this possibility. In particular, Germeshausen et al. discussed a potential role for digenicity in the phenotypic spectrum of SCN in their report of four individuals each with mutations in 2 separate candidate genes [24]. Mutations in additional candidate genes such as CSF3R, GFI1, WAS, and CXCR4 may also potentially contribute to the phenotypic spectrum, however these genes were not specifically examined in this case report [1]. The potential for modifier genes such as the transcription factors GFI1 and LEF-1 to impact clinical variability has also been proposed due their known ability upregulate expression of ELANE [25,26].

Conclusion

In conclusion, this patient’s mutation in ELANE may not have led to clinically significant neutropenia. However, in conjunction with the compound heterozygous COH1 mutations, the patient developed neutropenia that was more severe than what is typically seen in Cohen syndrome. Based on this we encourage consideration of additional candidate genes when an identified genetic mutation cannot fully explain the scope or severity of the clinical picture. Recognition of all mutations impacting a clinical phenotype will not only help achieve a more comprehensive diagnosis, but it will also help us gain a deeper understanding of the condition at hand.

Acknowledgement

We thank the family for their patience and support. The study was supported in part by Leonard Krieger Fund of the Cleveland Foundation (L2009-0078) and the William Bingham Foundation. We would also like to thank the staff of DDC clinic for their invaluable assistance in completion of this case report; in particular, Patti Gallagher, Chris Wensel, Karan Cechner, and Julia Szekely.

Grants/Financial Support

This work was supported by Leonard Krieger Fund of the Cleveland Foundation (L2009-0078) and William Bingham Foundation.

Disclosure of conflicts of interest

The authors have no conflicts of interest.

References



























Figures at a glance

Figure
Figure 1
Select your language of interest to view the total content in your interested language
Post your comment

Share This Article

Relevant Topics

Recommended Conferences

Article Usage

  • Total views: 7950
  • [From(publication date):
    December-2015 - Jun 25, 2017]
  • Breakdown by view type
  • HTML page views : 7877
  • PDF downloads :73

Review summary

  1. Uhrlaub L
    Posted on Jul 15 2016 at 3:15 am
    Beene and colleagues have reported a case study where mutations in ELANE and COH1 (VPS13B) genes cause severe neutropenia in a patient with Cohen Syndrome. This is certainly an interesting case to be reported considering that the mutations in COH1 are not previously reported in association with this disease. The manuscript presented an argument for the potential role of a previously reported mutation in ELANE in conjunction with mutations in COH1 could explain the severity with which a patient suffered from neutropenia.
 

Post your comment

captcha   Reload  Can't read the image? click here to refresh

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords