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Chediak– H igashi syndrome: description of two novel homozygous missense mutations causing divergent clinical phenotype
Author(s) -
SánchezGuiu Isabel,
Antón Ana I.,
GarcíaBarberá Nuria,
NavarroFernández José,
Martínez Constantino,
Fuster Jose L.,
Couselo Jose M.,
Ortuño Francisco J.,
Vicente Vicente,
Rivera Jose,
Lozano Maria L.
Publication year - 2014
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.12203
Subject(s) - missense mutation , phenotype , mutant , allele , genetics , mutation , gene , mutant protein , genotype , biology , microbiology and biotechnology
Chediak– H igashi syndrome ( CHS ) is a rare autosomal recessive disease resulting from mutations in the LYST / CHS 1 gene, which encodes for a 429 kD a protein, CHS 1/ LYST , that regulates vesicle trafficking and determines the size of lysosomes and other organelles. To date, 60 different mutations have been characterized, and a reasonably straightforward phenotype–genotype correlation has been suggested. We describe two patients on opposite ends of the CHS clinical spectrum with novel missense mutations. We characterized these patients in terms of their mutations, protein localization and expression, mRNA stability, and electrostatic potential. Patient 1 is the first report of a severe early‐onset CHS with a homozygous missense mutation (c.11362 G > A , p. G 3725 R ) in the LYST / CHS1 gene. This molecular change results in a reduction at the CHS 1 protein level, not due to an mRNA effect, but maybe a consequence of both, a change in the structure of the protein and most likely attributable to the remarkable serious perturbation in the electrostatic potential. Patient 2, who exhibited the adolescence form of the disease, was found to be homozygous for a novel missense mutation c.961 T > C , p. C 258 R , which seemed to have minor effect on the structure of the CHS 1/ LYST protein. Reexamining accepted premises of missense mutant alleles being reported among patients with clinically mild forms of the disorder should be carried out, and attempts to link genotype and clinical phenotype require identifying the actual molecular effect of the mutation. Early and accurate diagnosis of the severity of the disease is extremely important to early differentiate patients who would benefit from premature enrollment into a transplantation protocol.