Recessively inherited right atrial isomerism caused by mutations in growth/differentiation factor 1 (GDF1).
Right atrial isomerism (RAI) is a heterotaxy syndrome with disturbances in the left-right axis development, resulting in complex heart malformations and abnormal lateralization of other thoracic and abdominal organs. Although autosomal-recessive inheritance of heterotaxy syndrome is seen in multiple families, underlying gene defects have remained unknown. Here we identify the molecular genetic basis of a kindred with five siblings with RAI. Linkage analysis and positional candidate gene approach showed that the affected children were compound heterozygotes for truncating mutations in the growth/differentiation factor 1 (GDF1) gene. Individuals heterozygous for the mutations were clinically healthy. This finding, supported by the similar phenotype in Gdf1 knockout mouse, provides firm evidence that RAI can occur as a recessively inherited condition, with GDF1 as the culprit gene. The results will shed light on the biological basis of human laterality defects and facilitate molecular diagnosis of RAI.
Kaasinen
Eevi
E
Department of Medical Genetics, University of Helsinki, Helsinki 00014, Finland.
Aittomäki
Kristiina
K
Eronen
Marianne
M
Vahteristo
Pia
P
Karhu
Auli
A
Mecklin
Jukka-Pekka
JP
Kajantie
Eero
E
Aaltonen
Lauri A
LA
Lehtonen
Rainer
R
D000595:Amino Acid Sequence; D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D055452:Growth Differentiation Factor 1 / Q000235:genetics* / Q000502:physiology; D006325:Heart Atria / Q000002:abnormalities; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D011247:Pregnancy; D012857:Situs Inversus / Q000235:genetics
C525977:GDF1 protein, human; D055452:Growth Differentiation Factor 1