RGD Reference Report - SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. - Rat Genome Database

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SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.

Authors: Ruf, RG  Xu, PX  Silvius, D  Otto, EA  Beekmann, F  Muerb, UT  Kumar, S  Neuhaus, TJ  Kemper, MJ  Raymond RM, JR  Brophy, PD  Berkman, J  Gattas, M  Hyland, V  Ruf, EM  Schwartz, C  Chang, EH  Smith, RJ  Stratakis, CA  Weil, D  Petit, C  Hildebrandt, F 
Citation: Ruf RG, etal., Proc Natl Acad Sci U S A. 2004 May 25;101(21):8090-5. Epub 2004 May 12.
RGD ID: 8554876
Pubmed: PMID:15141091   (View Abstract at PubMed)
PMCID: PMC419562   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0308475101   (Journal Full-text)

Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal dominant developmental disorder characterized by hearing loss. In branchio-oto-renal (BOR) syndrome, malformations of the kidney or urinary tract are associated. Haploinsufficiency for the human gene EYA1, a homologue of the Drosophila gene eyes absent (eya), causes BOR and BO syndromes. We recently mapped a locus for BOR/BO syndrome (BOS3) to human chromosome 14q23.1. Within the 33-megabase critical genetic interval, we located the SIX1, SIX4, and SIX6 genes, which act within a genetic network of EYA and PAX genes to regulate organogenesis. These genes, therefore, represented excellent candidate genes for BOS3. By direct sequencing of exons, we identified three different SIX1 mutations in four BOR/BO kindreds, thus identifying SIX1 as a gene causing BOR and BO syndromes. To elucidate how these mutations cause disease, we analyzed the functional role of these SIX1 mutations with respect to protein-protein and protein-DNA interactions. We demonstrate that all three mutations are crucial for Eya1-Six1 interaction, and the two mutations within the homeodomain region are essential for specific Six1-DNA binding. Identification of SIX1 mutations as causing BOR/BO offers insights into the molecular basis of otic and renal developmental diseases in humans.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
branchiootorenal syndrome  IAGP 8554876DNA:missense mutations more ...RGD 
branchiootorenal syndrome  ISOSIX1 (Homo sapiens)8554876; 8554876DNA:missense mutations more ...RGD 
Hearing Loss  IAGP 8554876DNA:mutation:cds:c.373G >A(p.E125K)(human)RGD 
Hearing Loss  ISOSIX1 (Homo sapiens)8554876; 8554876DNA:mutation:cds:c.373G >A(p.E125K)(human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Six1  (SIX homeobox 1)

Genes (Mus musculus)
Six1  (sine oculis-related homeobox 1)

Genes (Homo sapiens)
SIX1  (SIX homeobox 1)


Additional Information