Novel Mutations of the ALMS1 Gene in Patients with Alström Syndrome

Abstract

Objective Alström syndrome is an autosomal recessive genetic disease caused by a mutation in the ALMS1 gene. Alström syndrome is clinically characterized by multisystem involvement, including sensorineural deafness, cone-rod dystrophy, nystagmus, obesity, insulin resistance, type 2 diabetes and hypogonadism. The diagnosis is thus challenging for patients without this characteristic set of clinical symptoms. We explored the effectiveness of whole-exome sequencing in the diagnosis of Alström syndrome. Methods A girl with symptoms of Alström syndrome was tested and diagnosed with the disease by whole-exome sequencing. Results Whole-exome sequencing revealed two novel variants, c.6160_6161insAT: p.Lys2054Asnfs*21 (exon 8) and c.10823_10824 delAG:p.Glu 3608Alafs*9 (exon16) in the ALMS1 gene, leading to premature termination codons and the domain of ALMS1 protein. Blood sample testing of her asymptomatic parents revealed them to be heterozygous carriers of the same mutations. Assembly showed that the mutations on both alleles were located in conserved sequences. A review of the ALMS1 gene nonsense mutation status was performed. Conclusion We herein report two novel variants of the ALMS1 gene discovered in a Chinese Alström syndrome patient that expand the mutational spectrum of ALMS1 and provided new insight into the molecular mechanism underlying Alström syndrome. Our findings add to the current knowledge concerning the diagnosis and treatment of Alström syndrome.

Keywords: ALMS1; Alström syndrome; mutations; nonsense mutation.

Figure 1.

Sanger sequencing results concerning the position of c.6160_6161insAT: p.Lys2054Asnfs*21on the ALMS1 gene. Electropherograms showing the DNA sequence at position c.6160_6161insAT: p.Lys2054Asnfs*21 of the ALMS1 gene in this patient (top). Her mother carried an insertion of AT in this position (bottom), whereas her father had normal findings (middle).

Figure 2.

Sanger sequencing results at the position of c.10823_10824 delAG: p.Glu3608Alafs*9 on the ALMS1 gene. Electropherograms showing the DNA sequence at position c.10823_10824 delAG: p.Glu3608Alafs*9 of the ALMS1 gene in this patient (top). Her father carried a deletion of AG in this position (middle), whereas her mother had normal findings (bottom).

Figure 3.

Sequence features of ALMS1. a: Represents the position of the exon of the ALMS1 gene and the mutation at the two sites in the exon. b: The N-terminal polyglutamate (PolyE) tract was polymorphic, CC: predicted coiled-coil domain, LZ: leucine zipper motif, pNLS: potential nuclear localization signal

Figure 4.

A comparison of the nonsense mutations on each exon of the ALMS1 gene.

Figure 5.

Conserved amino acid sequences of ALMS1 (amino acids 2,054 and 3,608).

Figure 6.

The Lys 2054 Asnfs*21 mutant structure was predicted by the I-TASSER server with default parameters. According to the protein sequence feature and the predicted structure, in the region between 625 and 2,200 amino acids, there were 32 fragment repeats, were most likely predicted as α-helix region.