Towards understanding the molecular basis of Alström syndrome

Gayle B. Collin1, Jan D. Marshall, Akihiro Ikeda, W Venus So, Isabelle Russell- Eggitt, Pietro Maffei, Sebastian Beck, Cornelius F. Boerkoel, Nicola Sicolo, Mitchell Martin, Patsy M. Nishina, Jürgen K. Naggert

Alström syndrome (AS), a homogeneous autosomal recessive disorder, is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia, and neurosensory deficits. Using a positional cloning strategy, we identified a novel transcript, KIAA0328, in which mutation analysis revealed sequence variations in patients with Alström syndrome. ALMS1 is a novel gene that is ubiquitously expressed at low levels and does not share significant sequence homology with other genes reported thus far. To date, we have identified mutations in 32 out of 62 kindreds screened. In total, 23 discrete nonsense and/or frameshift mutations have been observed, with the majority occurring in exon 16.

Subsets of Alström patients exhibit additional clinical features including dilated cardiomyopathy, hepatic dysfunction, hyperuricemia, hypothyroidism, male hypogonadism, short stature, and mild to moderate developmental delay. Phenotypic variation has also been observed within sibships which suggests that the disease manifestion of Alström syndrome is influenced by a combination of genetic and/or environmental factors. To dissect the genetic modifiers which interact with ALMS1, several mouse knockout models including a conditional knockout are being constructed in our laboratory. Mouse models are also being used to study the disease pathology and progression of AS. We have performed in situ hybridization and immunohistochemistry in various mouse tissues and in cell culture to elucidate the temporal and spatial expression pattern of ALMS1 . Studying the ALMS1 gene and determining the biochemical pathway in which it functions will assist toward a better understanding of both Alström syndrome and the common diseases that characterize it phenotypically.

1. The Jackson Laboratory, Bar Harbor, ME 04609, USA
2. Computational Genomics and Genetics, Hoffmann-La Roche, Inc., Nutley, NJ 07710, USA
3. Great Ormond Street Hospital, London, UK WCIN 3JH
4. Insituto di Semeiotica Medica, 35100 Padova, Italy
5. Insituto Nacional de Saude, P-1649-016 Lisbon, Portugal
6. Baylor College of Medicine, Houston, TX 77030, USA