UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis.
BACKGROUND
Familial hemophagocytic lymphohistiocytosis is a fatal disease characterized by immune dysregulation from defective function of cytotoxic lymphocytes. Three causative genes have been identified for this autosomal recessive disorder (PRF1, UNC13D, and STX11). We investigated the molecular genetics of familial hemophagocytic lymphohistiocytosis in Korea.


METHODS
Pediatric patients who fulfilled the HLH-2004 criteria were recruited from the Korean Registry for Histiocytosis. Molecular genetic studies were performed on the patients' DNA samples by direct sequencing of all coding exons and flanking sequences of PRF1, UNC13D, and STX11.


RESULTS
Forty patients were studied and familial hemophagocytic lymphohistiocytosis mutations were identified in nine; eight patients had UNC13D mutations (89%) and one had a mutation in PRF1. No patient had a STX11 mutation. Notably, four patients had only one UNC13D mutant allele, suggesting that the other mutation was missed by conventional direct sequencing. All UNC13D mutations were deleterious in nature. One known splicing mutation, c.754-1G>C, was recurrent, accounting for 58% of all the mutant alleles (7/12). Five UNC13D mutations were novel (p.Gln98X, p.Glu565SerfsX7, c.1993-2A>G, c.2367+1G>A, and c.2954+5G>A). The one patient with PRF1 mutation was homozygous for a frameshift mutation (p.Leu364GlufsX93), which was previously reported to be the most frequent PRF1 mutation in Japan.


CONCLUSIONS
This is the first investigation on the molecular genetics of familial hemophagocytic lymphohistiocytosis in Korea. The data showed that UNC13D is the predominant causative gene in the Korean population. The identification of mutations missed by conventional sequencing would better delineate the mutation spectrum and help to establish the optimal molecular diagnostic strategy for familial hemophagocytic lymphohistiocytosis in Korea, which might need an RNA-based screening strategy.
Yoon
Hoi Soo
HS
Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul, Korea.
Kim
Hee-Jin
HJ
Yoo
Keon-Hee
KH
Sung
Ki-Woong
KW
Koo
Hong-Hoe
HH
Kang
Hyoung Jin
HJ
Shin
Hee Young
HY
Ahn
Hyo Seop
HS
Kim
Ji-Yoon
JY
Lim
Young-Tak
YT
Bae
Keun-Wook
KW
Lee
Ki-O
KO
Shin
Ji-Sook
JS
Lee
Seung-Tae
ST
Chung
Hae-Sun
HS
Kim
Sun-Hee
SH
Park
Chan-Jeoung
CJ
Chi
Hyun-Sook
HS
Im
Ho-Joon
HJ
Seo
Jong Jin
JJ
D000293:Adolescent; D017398:Alternative Splicing / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000032:analysis / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007723:Korea; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics; D011379:Prognosis; D050765:Qa-SNARE Proteins / Q000235:genetics; D012008:Recurrence
D008565:Membrane Proteins; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D050765:Qa-SNARE Proteins; C541732:STX11 protein, human; C507969:UNC13D protein, human; D054353:Perforin; D004247:DNA