BACKGROUND: Congenital sideroblastic anemias are rare disorders with several genetic causes; they are characterized by erythroblast mitochondrial iron overload, differ greatly in severity and some occur within a syndrome. The most common cause of non-syndromic, microcytic sideroblastic anemia is a defect in the X-linked 5-aminolevulinate synthase 2 gene but this is not always present. Recently, variations in the gene for the mitochondrial carrier SLC25A38 were reported to cause a non-syndromic, severe type of autosomal-recessive sideroblastic anemia. Further evaluation of the importance of this gene was required to estimate the proportion of patients affected and to gain further insight into the range and types of variations involved. DESIGN AND METHODS: In three European diagnostic laboratories sequence analysis of SLC25A38 was performed on DNA from patients affected by congenital sideroblastic anemia of a non-syndromic nature not caused by variations in the 5-aminolevulinate synthase 2 gene. RESULTS: Eleven patients whose ancestral origins spread across several continents were homozygous or compound heterozygous for ten different SLC25A38 variations causing premature termination of translation (p.Arg117X, p.Tyr109LeufsX43), predicted splicing alteration (c.625G>C; p.Asp209His) or missense substitution (p.Gln56Lys, p.Arg134Cys, p.Ile147Asn, p.Arg187Gln, p.Pro190Arg, p.Gly228Val, p.Arg278Gly). Only three of these variations have been described previously (p.Arg117X, p.Tyr109LeufsX43 and p.Asp209His). All new variants reported here are missense and affect conserved amino acids. Structure modeling suggests that these variants may influence different aspects of transport as described for mutations in other mitochondrial carrier disorders. CONCLUSIONS: Mutations in the SLC25A38 gene cause severe, non-syndromic, microcytic/hypochromic sideroblastic anemia in many populations. Missense mutations are shown to be of importance as are mutations that affect protein production. Further investigation of these mutations should shed light on structure-function relationships in this protein.
BACKGROUND:Congenital sideroblastic anemias are rare disorders with several genetic causes; they are characterized by erythroblast mitochondrial iron overload, differ greatly in severity and some occur within a syndrome. The most common cause of non-syndromic, microcytic sideroblastic anemia is a defect in the X-linked 5-aminolevulinate synthase 2 gene but this is not always present. Recently, variations in the gene for the mitochondrial carrier SLC25A38 were reported to cause a non-syndromic, severe type of autosomal-recessive sideroblastic anemia. Further evaluation of the importance of this gene was required to estimate the proportion of patients affected and to gain further insight into the range and types of variations involved. DESIGN AND METHODS: In three European diagnostic laboratories sequence analysis of SLC25A38 was performed on DNA from patients affected by congenital sideroblastic anemia of a non-syndromic nature not caused by variations in the 5-aminolevulinate synthase 2 gene. RESULTS: Eleven patients whose ancestral origins spread across several continents were homozygous or compound heterozygous for ten different SLC25A38 variations causing premature termination of translation (p.Arg117X, p.Tyr109LeufsX43), predicted splicing alteration (c.625G>C; p.Asp209His) or missense substitution (p.Gln56Lys, p.Arg134Cys, p.Ile147Asn, p.Arg187Gln, p.Pro190Arg, p.Gly228Val, p.Arg278Gly). Only three of these variations have been described previously (p.Arg117X, p.Tyr109LeufsX43 and p.Asp209His). All new variants reported here are missense and affect conserved amino acids. Structure modeling suggests that these variants may influence different aspects of transport as described for mutations in other mitochondrial carrier disorders. CONCLUSIONS: Mutations in the SLC25A38 gene cause severe, non-syndromic, microcytic/hypochromic sideroblastic anemia in many populations. Missense mutations are shown to be of importance as are mutations that affect protein production. Further investigation of these mutations should shed light on structure-function relationships in this protein.
Authors: Robert D Finn; Jaina Mistry; John Tate; Penny Coggill; Andreas Heger; Joanne E Pollington; O Luke Gavin; Prasad Gunasekaran; Goran Ceric; Kristoffer Forslund; Liisa Holm; Erik L L Sonnhammer; Sean R Eddy; Alex Bateman Journal: Nucleic Acids Res Date: 2009-11-17 Impact factor: 16.971
Authors: Toshihiko Tanno; Natarajan V Bhanu; Patricia A Oneal; Sung-Ho Goh; Pamela Staker; Y Terry Lee; John W Moroney; Christopher H Reed; Naomi L C Luban; Rui-Hong Wang; Thomas E Eling; Richard Childs; Tomas Ganz; Susan F Leitman; Suthat Fucharoen; Jeffery L Miller Journal: Nat Med Date: 2007-08-26 Impact factor: 53.440
Authors: Anke K Bergmann; Dean R Campagna; Erin M McLoughlin; Suneet Agarwal; Mark D Fleming; Sylvia S Bottomley; Ellis J Neufeld Journal: Pediatr Blood Cancer Date: 2010-02 Impact factor: 3.167
Authors: Duane L Guernsey; Haiyan Jiang; Dean R Campagna; Susan C Evans; Meghan Ferguson; Mark D Kellogg; Mathieu Lachance; Makoto Matsuoka; Mathew Nightingale; Andrea Rideout; Louis Saint-Amant; Paul J Schmidt; Andrew Orr; Sylvia S Bottomley; Mark D Fleming; Mark Ludman; Sarah Dyack; Conrad V Fernandez; Mark E Samuels Journal: Nat Genet Date: 2009-05-03 Impact factor: 38.330
Authors: Toshihiko Tanno; Prashanth Porayette; Orapan Sripichai; Seung-Jae Noh; Colleen Byrnes; Ajoy Bhupatiraju; Y Terry Lee; Julia B Goodnough; Omid Harandi; Tomas Ganz; Robert F Paulson; Jeffery L Miller Journal: Blood Date: 2009-05-04 Impact factor: 22.113
Authors: Daniel H Wiseman; Alison May; Stephen Jolles; Philip Connor; Colin Powell; Matthew M Heeney; Patricia J Giardina; Robert J Klaassen; Pranesh Chakraborty; Michael T Geraghty; Nathalie Major-Cook; Caroline Kannengiesser; Isabelle Thuret; Alexis A Thompson; Laura Marques; Stephen Hughes; Denise K Bonney; Sylvia S Bottomley; Mark D Fleming; Robert F Wynn Journal: Blood Date: 2013-04-03 Impact factor: 22.113