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A novel nonsense mutation of the KAL1 gene (p.Trp204*) in Kallmann syndrome.

ABSTRACT: OBJECTIVE:To describe a novel KAL1 mutation in patients affected by Kallmann syndrome. SETTING:Endocrinology Clinic of the João de Barros Barreto University Hospital - Federal University of Pará, Brazil. METHODS:Clinical examination, hormone assays and sequencing of exons 5, 6 and 9 of the KAL1 gene in four Brazilian brothers with Kallmann syndrome. RESULTS:Detected a novel KAL1 mutation, c.612G.A/p.Trp204*, in four hemizygous brothers with Kallmann syndrome, and five heterozygous female family members. CONCLUSION:The novel p.Trp204* mutation of the KAL1 gene results in the production of a truncated anosmin-1 enzyme in patients with Kallmann syndrome. This finding broadens the spectrum of pathogenic mutations for this disease.

SUBMITTER: El Husny AS

PROVIDER: S-EPMC4196791 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A novel nonsense mutation of the KAL1 gene (p.Trp204*) in Kallmann syndrome.

El Husny Antonette Souto AS Raiol-Moraes Milene M Fernandes-Caldato Milena Coelho MC Ribeiro-Dos-Santos Andrea A

The application of clinical genetics 20140930

<h4>Objective</h4>To describe a novel KAL1 mutation in patients affected by Kallmann syndrome.<h4>Setting</h4>Endocrinology Clinic of the João de Barros Barreto University Hospital - Federal University of Pará, Brazil.<h4>Methods</h4>Clinical examination, hormone assays and sequencing of exons 5, 6 and 9 of the KAL1 gene in four Brazilian brothers with Kallmann syndrome.<h4>Results</h4>Detected a novel KAL1 mutation, c.612G.A/p.Trp204*, in four hemizygous brothers with Kallmann syndrome, and fiv ...[more]

PMID: 25328414

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Project description:BackgroundKallmann syndrome (KS) is a common type of idiopathic hypogonadotropic hypogonadism. To date, more than 30 genes including ANOS1 and FGFR1 have been identified in different genetic models of KS without affirmatory genotype-phenotype correlation, and novel mutations have been found.MethodsA total of 35 unrelated patients with clinical features of disorder of sex development were recruited. Custom-panel sequencing or whole-exome sequencing was performed to detect the pathogenic mutations. Sanger sequencing was performed to verify single-nucleotide variants. Copy number variation-sequencing (CNV-seq) was performed to determine CNVs. The pathogenicity of the identified variant was predicted in silico. mRNA transcript analysis and minigene reporter assay were performed to test the effect of the mutation on splicing.ResultsANOS1 gene c.709 T > A and c.711 G > T were evaluated as pathogenic by several commonly used software, and c.1063-2 A > T was verified by transcriptional splicing assay. The c.1063-2 A > T mutation activated a cryptic splice acceptor site downstream of the original splice acceptor site and resulted in an aberrant splicing of the 24-basepair at the 5' end of exon 8, yielding a new transcript with c.1063-1086 deletion. FRFR1 gene c.1835delA was assessed as pathogenic according to the ACMG guideline. The CNV of del(8)(p12p11.22)chr8:g.36140000_38460000del was judged as pathogenic according to the ACMG & ClinGen technical standards.ConclusionsHerein, we identified three novel ANOS1 mutations and two novel FGFR1 variations in Chinese KS families. In silico prediction and functional experiment evaluated the pathogenesis of ANOS1 mutations. FRFR1 c.1835delA mutation and del(8)(p12p11.22)chr8:g.36140000_38460000del were assessed as pathogenic variations. Therefore, our study expands the spectrum of mutations associated with KS and provides diagnostic evidence for patients who carry the same mutation in the future.

Dataset Information

A novel nonsense mutation of the KAL1 gene (p.Trp204*) in Kallmann syndrome.

Publications

A novel nonsense mutation of the KAL1 gene (p.Trp204*) in Kallmann syndrome.

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