letter 74 nature genetics • volume 31 • may 2002 Alström syndrome is a homogeneous autosomal recessive dis- order that is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia and neurosen- sory deficits 1,2 . The gene involved in Alström syndrome proba- bly interacts with genetic modifiers, as subsets of affected individuals present with additional features such as dilated car- diomyopathy 3 , hepatic dysfunction 4 , hypothyroidism 5 , male hypogonadism, short stature and mild to moderate develop- mental delay, and with secondary complications normally asso- ciated with type 2 diabetes, such as hyperlipidemia and atherosclerosis. Our detection of an uncharacterized transcript, KIAA0328, led us to identify the gene ALMS1, which contains sequence variations, including four frameshift mutations and two nonsense mutations, that segregate with Alström syn- drome in six unrelated families. ALMS1 is ubiquitously expressed at low levels and does not share significant sequence homology with other genes reported so far. The iden- tification of ALMS1 provides an entry point into a new path- way leading toward the understanding of both Alström syndrome and the common diseases that characterize it. We initially mapped ALMS1 within a region of 14.9 cM (ref. 6) on chromosome 2p13 in a large French Acadian kindred; we later refined the interval to 6.1 cM (refs 7,8). Further recombinational and physical mapping resolved the critical interval to less than 2cM, encompassing a region of 1.2 Mb (Fig. 1). We assembled the physical contig from publicly available sequence data (GenBank) by aligning overlapping BAC clones and adjoining fragments by transcription unit content. We identified candidate genes for mutation analysis by comparing the contig sequence with sequences of identified genes and expressed sequence tag (EST) clusters, using the NIX (UK Human Genome Mapping Project Resource Center) annotation pipeline and individual searches of the LifeSeq database (Incyte Genomics) and GenBank. We identi- fied 16 genes and EST clusters within the minimal interval (Fig. 1) and prioritized candidate genes based on their expression pattern and function. Genes that are known to be expressed in the eye (RAI15, a retinoic acid–responsive transcript) and genes that, based on their function, might be involved in obesity and retinal degeneration (the transcript KIAA0919, encoding a secretory pathway component, and CCT7, encoding a chaperonin) were screened first; we proceeded to carry out a systematic screening of all genes in the region. One EST cluster, including transcript KIAA0328, was composed of cDNA fragments expressed in many tissues that are affected in individuals with Alström syndrome. To obtain the full-length cod- ing sequence of this new gene, we aligned KIAA0328 with overlap- ping transcripts from the databases of Incyte Genomics, GenBank and The Institute for Genomic Research (TIGR). We initially pre- dicted a human cDNA sequence of 6,612 bp. Wilson et al. 9 report the identification of additional exons at the 5′ end of the gene in an accompanying paper. We confirmed the presence of these exons by sequence analysis of RT–PCR products from human and mouse (C57BL/6J) brain. We identified an additional exon (exon 2) in the D2S2110 D2S1394 D2S2111 D2S145 D2S2109 D2S1398 AC032022 AC023027 AC012366 AC010913 AC069404 AC074008 D2S1374 326WG9 AC069101 AC073046 16770GT 69346CA 73046GT 69101GT AC069346 ALMS 1 critical interval K1 K53 1 3 2 4 5 6 7 8 9–12 13 14 15 16 1. KIAA0919 9. CCT7 2. SPR 10. THC530316 3. EMX1 11. AI014261 4. THC529835 12. EGR4 5. KIAA0857 13. KIAA0328 6. THC551446* 14. DUSP11 7. EMX-related gene* 15. AMSH* 8. RAI15 16. ACTG2 markers BACs candidate genes Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome Gayle B. Collin 1 , Jan D. Marshall 1 , Akihiro Ikeda 1 ,W. Venus So 2 , Isabelle Russell-Eggitt 3 , Pietro Maffei 4 , Sebastian Beck 5 , Cornelius F. Boerkoel 6 , Nicola Sicolo 4 , Mitchell Martin 2 , Patsy M. Nishina 1 & Jürgen K. Naggert 1 1 The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. 2 Computational Genomics and Genetics, Hoffmann-La Roche Inc., Nutley, New Jersey, USA. 3 Great Ormond Street Hospital, London, UK. 4 Istituto di Semeiotica Medica, Padova, Italy. 5 Instituto Nacional de Saude, Lisbon, Portugal. 6 Baylor College of Medicine, Houston, Texas, USA. Correspondence should be addressed to J.K.N. (e-mail: jkn@jax.org). Published online: 8 April 2002, DOI: 10.1038/ng867 Fig. 1 Fine-resolution and physical maps of the ALMS1 region. Recombinations in an affected child from the French Acadian Kindred 1 and a child from a small nuclear family, Kindred 53, place the ALMS1 critical interval in a region of less than 2 cM. Affected haplotypes are shown as darkened bars. Eight over- lapping BACs complete a 1.2-Mb contig. Locations of 16 known and predicted genes identified from EST clusters are shown as darkened bars. Genes not tested for mutation analysis are depicted with an asterisk. 1–16: EST (KIAA0919), SPR (sepiapterin reductase), EMX1 (empty spiracle, drosophila homolog 1), THC529835 (Caenorhabditis elegans sre2 homolog), EST (KIAA0857), EST (THC551446), a predicted gene related to EMX homeobox protein, RAI15 (retinoic acid–induced 15), CCT7 (chaperonin containing TCP1, subunit 7), EST (THC530316), EST (AI014261), EGR4 (early growth response 4), EST (KIAA0328), DUSP11 (dual-specificity phosphatase 11), AMSH (STAM-asso- ciated molecule) and ACTG2 (actin, γ-2, smooth muscle, enteric). © 2002 Nature Publishing Group http://genetics.nature.com