Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III

Abstract

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

Figure 1

Pedigrees of familial cases of TRPS. Cases are shown in the order in which they appear in table 1. Affected individuals are indicated by blackened symbols. Individuals available for sequence analysis are denoted with bars above the symbol.

Figure 2

Structure of the TRPS1 protein and location of mutations. Hatched boxes, zinc-finger motifs (zf). Vertical bars, putative nuclear localization signals (NLSs). The location of the GATA and IKAROS-like zinc fingers are given. Blackened triangles indicate the localization of the premature stop codons, and missense mutations are indicated by arrows. The effect of the splice site mutation, skipping of exon 6, is denoted by an unblackened triangle. Recurrent mutations are identified by an asterisk (*). Note that two different insertion mutations lead to a premature stop codon at amino acid (aa) 830 and that we found two different missense mutation at aa 908.

Figure 3

Splice-site mutation in patient 13568. A, Agarose gel with products of RT-PCR of RNA from the patient's leukocytes. The upper band (1,067 bp) is derived from the normal transcript and the lower band (944 bp) from the mutant transcript. M = length standard (1 Kb DNA ladder, Gibco BRL). B, Sequence analysis of the RT-PCR product from the mutant transcript. Exon 5 is spliced to exon 7. One putative NLS (LRRRRG, in italics) is truncated, and the GATA zinc finger is completely absent in the mutant protein.

Figure 4

MCPP analyses in TRPS. A, Spectrum of MCPPs of patients with different TRPS1 mutations. B, Comparison of mean pattern profiles (see text). C, MCPPs of mother (individual II-2) and daughter (III-1) of family 13333 show no significant correlation (r=0.38).