Structures of human OX40 and CD27 and locations of clinically described mutations. Schematic of full-length human OX40 and CD27 (including the signal peptides), showing CRDs 1, 2, 3, and in the case of OX40 also CRD 4 in progressively lighter shades of blue with positions of the CRDs shown as defined from crystallographic studies. Residues within the extracellular region of the receptor but that do not fall within a CRD are indicated by a vertical line, the transmembrane regions are shown in gray, and cytoplasmic residues are represented in pink. Amino acid numbers are indicated, and positions of cysteine residues within the CRDs are shown by a horizontal line. Positions of mutations described in patients and their impact on receptor expression where known are also shown. Why a heterozygous C10X mutation should result in absent CD27 expression is unclear; the C10X heterozygous mutation in the patient’s father resulted in only partial loss of CD27. It is likely that the patient’s mother, who also exhibited defects in CD27 expression, carries an unidentified mutation elsewhere in the genome (no mutations could be identified in the CD27 locus) that causes suboptimal CD27 expression. Thus, in reality the patient is likely to be a compound heterozygote having inherited the C10X mutation from her father and an unknown mutation from her mother (see Alkhairy et al³⁵ ).