Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene

Abstract

Multiple-lentigines (ML)/LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is an autosomal dominant condition--characterized by lentigines and café au lait spots, facial anomalies, cardiac defects--that shares several clinical features with Noonan syndrome (NS). We screened nine patients with ML/LEOPARD syndrome (including a mother-daughter pair) and two children with NS who had multiple café au lait spots, for mutations in the NS gene, PTPN11, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the PTPN11 phosphotyrosine phosphatase domain, which is involved in <30% of the NS PTPN11 mutations. The study demonstrates that ML/LEOPARD syndrome and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS.

Figure 1

Facial appearance of patient 2

Figure 2

SSCP and sequence analysis of the two identified mutations. Anomalous patterns of DNA SSCP in patients with ML/LEOPARD syndrome are indicated by asterisks (*). a, Mutation 836A→G in exon 7. b, Mutation 1403C→T in exon 12.

Figure 3

PTPN11 protein structure and location of the two missense mutations reported. N-SH2 and C-SH2 are the N-terminal and C-terminal tandemly arranged SH2 domains, followed by a protein PTP domain at the C-terminus, where the two mutational hotspots are localized. Functional domains' amino acid boundaries are indicated.

Figure 4

Structure of PTPN11 protein representation with mutated amino acids. Cα-traces of the N-SH2 (green), C-SH2 (clear green), and PTP (red) domains are shown. Mutated residues are indicated by thick lines. Most mutations (thick, white lines) in patients with NS who have been described elsewhere (Tartaglia et al. 2001) are located in the N-SH2 domain. The ML/LEOPARD mutations (thick, cyan lines) are located in the PTP domain. This model was made by use of the program Deep View Swiss-PdbViewer.