Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin

• Published in: American journal of human genetics Vol. 90; no. 1; pp. 61 - 68
• Main Authors: Huppke, Peter, Brendel, Cornelia, Kalscheuer, Vera, Korenke, Georg Christoph, Marquardt, Iris, Freisinger, Peter, Christodoulou, John, Hillebrand, Merle, Pitelet, Gaele, Wilson, Callum, Gruber-Sedlmayr, Ursula, Ullmann, Reinhard, Haas, Stefan, Elpeleg, Orly, Nürnberg, Gudrun, Nürnberg, Peter, Dad, Shzeena, Møller, Lisbeth Birk, Kaler, Stephen G., Gärtner, Jutta
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 13.01.2012; Cell Press; Elsevier
• Subjects: Base Sequence; Biological and medical sciences; Cataract - congenital; Cataract - genetics; Cerebellum - abnormalities; Cerebellum - growth & development; Ceruloplasmin - analysis; Ceruloplasmin - metabolism; Child; Child, Preschool; Chromosome Mapping; Chromosomes, Human, Pair 3 - genetics; Copper; Copper - blood; Enzymes; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic disorders; Genetic research; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Hearing Loss - congenital; Hearing Loss - genetics; Hep G2 Cells; Humans; Infant; Lens diseases; Male; Medical genetics; Medical sciences; Membrane Transport Proteins - biosynthesis; Membrane Transport Proteins - genetics; Molecular and cellular biology; Molecular Sequence Data; Mutation; Mutation - genetics; Ophthalmology; Proteins; Severity of Illness Index; Human; Cataract; Congenital; Auditory disorder; Genetic disease; Hearing loss; Eye disease; Lens disease; Low; Autosomal character; ENT disease; Recessive character; Genetics; Serum; Mutation; Copper; Anterior segment disease
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2011.11.030

Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum.