Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome.
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10-15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the CHS1 gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant CHS1 alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode CHS1 polypeptides with partial function. Together, these results suggest an allelic genotype-phenotype relationship among the various clinical forms of CHS.
Karim
Mohammad A
MA
Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Suzuki
Koji
K
Fukai
Kazuyoshi
K
Oh
Jangsuk
J
Nagle
Deborah L
DL
Moore
Karen J
KJ
Barbosa
Ernest
E
Falik-Borenstein
Tzipora
T
Filipovich
Alexandra
A
Ishida
Yasushi
Y
Kivrikko
Sirpa
S
Klein
Christoph
C
Kreuz
Friedmar
F
Levin
Alex
A
Miyajima
Hiroaki
H
Regueiro
Jose R
JR
Russo
Carolyn
C
Uyama
Eiichiro
E
Vierimaa
Outi
O
Spritz
Richard A
RA
D000293:Adolescent; D000328:Adult; D002609:Chediak-Higashi Syndrome / Q000235:genetics* / Q000503:physiopathology; D002675:Child, Preschool; D022202:Chromosomes, Artificial, Bacterial; D027042:Chromosomes, Artificial, P1 Bacteriophage; D018389:Codon, Nonsense; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D005091:Exons; D016368:Frameshift Mutation; D005656:Fungal Proteins / Q000235:genetics*; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007438:Introns; D020125:Mutation, Missense; D010641:Phenotype; D017422:Sequence Analysis, DNA
C430064:CSH1 protein, Candida albicans; D018389:Codon, Nonsense; D005656:Fungal Proteins