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A six-generation kindred from Arkansas with X-linked recessive spondyloepiphyseal dysplasia tarda (SEDT) was investigated by genetic linkage and mutation analysis. SEDT had been mapped on the X-chromosome (Xp22.2), and the clinical and radiographic evolution of this kindred had been published. Linkage analysis proved informative for all five polymorphic markers tested, and DXS987 and DXS16 co-segregated with the Arkansas kindred (peak logarithm of the odds scores, 3.54 and 3.36, respectively). Subsequently, dinucleotide deletion in a new gene designated "sedlin" was reported to cause SEDT in three families. In an affected man and obligate carrier woman in the Arkansas kindred, we found a 5-bp deletion in exon 5 of sedlin. The defect causes a frameshift, resulting in eight missense amino acids and premature termination. The 5-bp deletion was then demonstrated to segregate with SEDT in the four living generations, including eight affected males and nine obligate carrier females. Furthermore, the deletion was identified in four females who potentially were heterozygous carriers for SEDT. The mutation was not detected in the two young sons of the consultand (believed to be a carrier because of her subtle radiographic skeletal changes and then shown to have the deletion), but they were too young for x-ray diagnosis Identification of a defect in sedlin in this SEDT kindred enables carrier detection and presymptomatic diagnosis and reveals an important role for this gene in postnatal endochondral bone formation.

Original publication

DOI

10.1210/jcem.85.9.6840

Type

Journal article

Journal

J Clin Endocrinol Metab

Publication Date

09/2000

Volume

85

Pages

3343 - 3347

Keywords

Adult, Carrier Proteins, Chromosomes, Human, Pair 22, DNA, Exons, Female, Genetic Linkage, Heterozygote, Humans, Male, Membrane Transport Proteins, Mutation, Osteochondrodysplasias, Pedigree, Phenotype, Reverse Transcriptase Polymerase Chain Reaction, Sequence Deletion, Transcription Factors