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Chediak-Higashi Syndrome

Written2012-12Xinjie Xu, Wei Shen
Cytogenetics Laboratory, Center for Human Genetics, Inc, Cambridge, MA, USA (XX); Waisman Center, University of Wisconsin-Madison, Madison, WI, USA (WS)

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Identity

Other namesCHS
Atlas_Id 10128
Genes implicated inLYST  
Note Chediak-Higashi Syndrome is a rare genetic disease. The clinical features include oculocutaneous albinism, immunodeficiency, neurological manifestations, mild coagulation defects and a predisposition to lymphoma-like cancer.
Inheritance Autosome Recessive.

Clinics

Phenotype and clinics The symptoms of CHS patients are variable. They have highly variable hypopigmentation of the skin, eye and hair (oculocutaneus albinism). The Neurological manifestations are also variable, including cognitive impairment, peripheral neuropathy, ataxia, and parkinsonism. In addition, the CHS patients have frequent infections, particularly bacterial infections of the skin and respiratory tract. Symptoms can appear anytime from childhood to early adulthood. Generally speaking, CHS patients have mild coagulation defects including epistaxis, gum/mucosal bleeding, and easy bruising.
The accelerated phase, which occurs in 85% of individuals with CHS, can take place at any age. Clinical manifestations include fever, lymphadenopathy, hepatosplenomegaly, anemia, neutropenia, and sometimes thrombocytopenia. Originally thought to be a malignancy resembling lymphoma, the accelerated phase is now known to be a hemophagocytic lymphohistiocytosis characterized by multiorgan inflammation. The accelerated phase and its complications are the most common causes of mortality in CHS patients.
Most CHS patients present in early childhood and die unless treated by bone marrow transplantation. About 10-15% of patients exhibit a much milder clinical symptoms and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, with severe infections in early childhood, but a milder course by adolescence, and no accelerated phase.
Treatment Infections are treated with antibiotics. Antiviral drugs such as acyclovir and chemotherapy drugs are often used in the accelerated phase of the disease. Surgery may be needed to drain abscesses in some cases.
Patients in the accelerated phase are treated with chemoimmunotherapy followed by transition to continuation therapy. Allogenic HSCT is the only treatment to cure hematologic and immunologic defects. Platelet transfusions are needed for serious bleeding. Corrective lenses help to improve visual acuity. Treatment by rehabilitation specialists are used for neurologic complications.
Prognosis CHS patients usually die in their first decade of life, from chronic infections or accelerated disease. However, some mildly affected children have survived longer.

Genes involved and Proteins

Gene NameLYST (lysosomal trafficking regulator)
Location 1q42.3
DNA/RNA
 
  
Description 55 exons spanning 205.9 kb of genomic DNA.
Transcription Two alternative transcriptions. The large transcript (12.0 kb) produces functional protein. The function of the small transcript (5.8 kb) is unknown.
Protein
 
  
Description The CHS protein is composed of 3801 amino acids. The molecular weight of the CHS protein is 430 kDa. The N-terminus of the protein has a large stretch of alpha-helices termed HEAT repeats (Figure 2). HEAT repeats are important to mediate membrane associations and are associated with vesicle transport. The C-terminus of the protein has two domains that are conserved between the human and mouse homologues. The first of these domains has been referred to as the BEACH domain. The BEACH domain contains a consensus 'WIDL' amino acid stretch as well as several other conserved amino acids that define members of the CHS protein family. The second domain contains a WD-40 repeat region, indicative of a protein-protein interaction domain.
Expression LYST is expressed in all cells.
Localisation Cytosolic.
Function Lysosome trafficking regulator.
Homology There are 82% identity and 88% homology between the human and mouse proteins. Similar degrees of identity are seen among human, rat and cow CHS genes.
Mutations
Note More than 50 mutations have been identified, most of which are nonsense mutations that result in premature stop codons and thus a truncated protein. Figure 1 shows the distribution of the mutations.

Bibliography

Hematopoietic cell transplantation for Chediak-Higashi syndrome.
Eapen M, DeLaat CA, Baker KS, Cairo MS, Cowan MJ, Kurtzberg J, Steward CG, Veys PA, Filipovich AH.
Bone Marrow Transplant. 2007 Apr;39(7):411-5. Epub 2007 Feb 12.
PMID 17293882
 
Hermansky-Pudlak syndrome and Chediak-Higashi syndrome: disorders of vesicle formation and trafficking.
Huizing M, Anikster Y, Gahl WA.
Thromb Haemost. 2001 Jul;86(1):233-45. (REVIEW)
PMID 11487012
 
Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome.
Introne W, Boissy RE, Gahl WA.
Mol Genet Metab. 1999 Oct;68(2):283-303. (REVIEW)
PMID 10527680
 
Chediak-Higashi Syndrome.
Introne WJ, Westbroek W, Golas GA, Adams D.
In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.2009 Mar 03 [updated 2012 Feb 16].
PMID 20301751
 
Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome.
Karim MA, Suzuki K, Fukai K, Oh J, Nagle DL, Moore KJ, Barbosa E, Falik-Borenstein T, Filipovich A, Ishida Y, Kivrikko S, Klein C, Kreuz F, Levin A, Miyajima H, Regueiro J, Russo C, Uyama E, Vierimaa O, Spritz RA.
Am J Med Genet. 2002 Feb 15;108(1):16-22.
PMID 11857544
 
Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome.
Nagle DL, Karim MA, Woolf EA, Holmgren L, Bork P, Misumi DJ, McGrail SH, Dussault BJ Jr, Perou CM, Boissy RE, Duyk GM, Spritz RA, Moore KJ.
Nat Genet. 1996 Nov;14(3):307-11.
PMID 8896560
 
Analysis of the lysosomal storage disease Chediak-Higashi syndrome.
Ward DM, Griffiths GM, Stinchcombe JC, Kaplan J.
Traffic. 2000 Nov;1(11):816-22. (REVIEW)
PMID 11208072
 

Citation

This paper should be referenced as such :
Xu, X ; Shen, W
Chediak-Higashi Syndrome
Atlas Genet Cytogenet Oncol Haematol. 2013;17(5):364-366.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/ChediakHigashiID10128.html


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