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. DESIGN AND 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.
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. DESIGN AND 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.
Authors: K Göransdotter Ericson; B Fadeel; S Nilsson-Ardnor; C Söderhäll; A Samuelsson; G Janka; M Schneider; A Gürgey; N Yalman; T Révész; R Egeler; K Jahnukainen; I Storm-Mathiesen; A Haraldsson ; J Poole; G de Saint Basile; M Nordenskjöld; J Henter Journal: Am J Hum Genet Date: 2001-02-06 Impact factor: 11.025
Authors: K Yamamoto; E Ishii; M Sako; S Ohga; K Furuno; N Suzuki; I Ueda; M Imayoshi; S Yamamoto; A Morimoto; H Takada; T Hara; S Imashuku; T Sasazuki; M Yasukawa Journal: J Med Genet Date: 2004-10 Impact factor: 6.318
Authors: R Clementi; U zur Stadt; G Savoldi; S Varoitto; V Conter; C De Fusco; L D Notarangelo; M Schneider; C Klersy; G Janka; C Danesino; M Aricò Journal: J Med Genet Date: 2001-09 Impact factor: 6.318
Authors: Jae Yeon Kim; Jeong Hee Shin; Se In Sung; Jin Kyu Kim; Ji Mi Jung; So Yoon Ahn; Eun Sun Kim; Ja-Young Seo; Eun-Sook Kang; Sun-Hee Kim; Hee-Jin Kim; Yun Sil Chang; Won Soon Park Journal: Korean J Pediatr Date: 2014-01-31
Authors: Ali Al Ahmari; Osama Alsmadi; Atia Sheereen; Tanziel Elamin; Amal Jabr; Lina El-Baik; Safa Alhissi; Bandar Al Saud; Moheeb Al-Awwami; Ibrahim Al Fawaz; Mouhab Ayas; Khawar Siddiqui; Abbas Hawwari Journal: Blood Res Date: 2021-06-30