A Novel A461S Mutation of PTPN11 in a Female with LEOPARD Syndrome.

Introduction

LEOPARD syndrome (LS) is a congenital developmental disorder and is an acronym for multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness (1). These clinical features overlap those of Noonan syndrome (NS), and heterozygous germline PTPN11 mutations have been identified in approximately 45% of NS patients and in >80% of LS patients (1). Herein, we report a novel mutation of PTPN11 in a female with LS.

Patient Report

A 34-year-old Japanese female was referred to us for molecular diagnosis of LS. She had numerous nevi, ocular hypertelorism, cardiac diseases (mitral valve insufficiency and right bundle branch block with left axis deviation) and sensorineural deafness. Her height was 160 cm (+0.4 SD), and her weight was 62 kg (+1.0 SD). This study was approved by the ethical committee of our institution. After obtaining informed consent, direct sequencing was performed for PTPN11 using leukocyte genomic DNA from this patient in accordance with previously reported methods (2). Consequently, a novel heterozygous c.1381G>T (p.A461S) mutation was identified on exon 12 (Fig. 1).

Fig. 1.

An electrochromatogram showing a heterozygous c.1381G>T (p.A461S) mutation (an arrow).

Discussion

We identified a novel mutation (c.1381G>T, p.A461S) of PTPN11 in a female with LS. Recent studies have shown that LS-associated PTPN11 mutants impair catalytic functions and exert dominant negative effects, whereas NS-associated PTPN11 mutants exert gain-of-function effects with excessive phosphatase activities (1, 3). Indeed, the mutations in LS and NS are mutually exclusive, and all eleven types of mutation in LS (two recurrent Y279C and T468M mutations and additional Y279S, A461T, T468P, G464A, R498L, R498W, Q506P, Q510E and Q510P mutations) have been identified at the catalytic cleft of the PTPN11 protein (1, 3,4,5) (Fig. 2). Since the novel c.1381G>T (p.A461S) mutation in this patient also resides at the catalytic cleft, this is consistent with the positional properties of PTPN11 mutations leading to LS.

Fig. 2.

Schematic representation of PTPN11 protein showing the distribution of mutations reported in LS (above). The position of the mutation detected in this study is also indicated (below). N-SH2 and C-SH2 are the N-terminal and C-terminal tandemly arranged SH2 domains and are followed by a protein PTP domain at the C-terminus.