title: Variations of the UNC13D gene in patients with autoimmune lymphoproliferative syndrome.
abstract: Autoimmune lymphoproliferative syndrome (ALPS) is caused by genetic defects decreasing Fas function and is characterized by lymphadenopathy/splenomegaly and expansion of CD4/CD8 double-negative T cells. This latter expansion is absent in the ALPS variant named Dianzani Autoimmune/lymphoproliferative Disease (DALD). In addition to the causative mutations, the genetic background influences ALPS and DALD development. We previously suggested a disease-modifying role for the perforin gene involved in familial hemophagocytic lymphohistiocytosis (FHL). The UNC13D gene codes for Munc13-4, which is involved in perforin secretion and FHL development, and thus, another candidate for a disease-modifying role in ALPS and DALD. In this work, we sequenced UNC13D in 21 ALPS and 20 DALD patients and compared these results with sequences obtained from 61 healthy subjects and 38 multiple sclerosis (MS) patients. We detected four rare missense variations in three heterozygous ALPS patients carrying p.Cys112Ser, p.Val781Ile, and a haplotype comprising both p.Ile848Leu and p.Ala995Pro. Transfection of the mutant cDNAs into HMC-1 cells showed that they decreased granule exocytosis, compared to the wild-type construct. An additional rare missense variation, p.Pro271Ser, was detected in a healthy subject, but this variation did not decrease Munc13-4 function. These data suggest that rare loss-of-function variations of UND13D are risk factors for ALPS development.
authors.affiliation: Department of Pediatric Hematology Oncology, Meyer Children Hospital, Firenze, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Aricò
authors.forename: Elena
authors.initials: E
authors.lastname: Boggio
authors.forename: Valentina
authors.initials: V
authors.lastname: Cetica
authors.forename: Matteo
authors.initials: M
authors.lastname: Melensi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orilieri
authors.forename: Nausicaa
authors.initials: N
authors.lastname: Clemente
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cappellano
authors.forename: Sara
authors.initials: S
authors.lastname: Buttini
authors.forename: Maria Felicia
authors.initials: MF
authors.lastname: Soluri
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Comi
authors.forename: Carlo
authors.initials: C
authors.lastname: Dufour
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.forename: Irma
authors.initials: I
authors.lastname: Dianzani
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ellis
authors.forename: Sara
authors.initials: S
authors.lastname: Pagliano
authors.forename: Stefania
authors.initials: S
authors.lastname: Marcenaro
authors.forename: Ugo
authors.initials: U
authors.lastname: Ramenghi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
mesh_terms: D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics*; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics; D020125:Mutation, Missense
chemical_list: D008565:Membrane Proteins; C507969:UNC13D protein, human