title: Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome.
abstract: Germline mutations in PTPN11--the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2--represent a major cause of Noonan syndrome (NS), a developmental disorder characterized by short stature and facial dysmorphism, as well as skeletal, hematologic, and congenital heart defects. Like many autosomal dominant disorders, a significant percentage of NS cases appear to arise from de novo mutations. Here, we investigated the parental origin of de novo PTPN11 lesions and explored the effect of paternal age in NS. By analyzing intronic portions that flank the exonic PTPN11 lesions in 49 sporadic NS cases, we traced the parental origin of mutations in 14 families. Our results showed that all mutations were inherited from the father, despite the fact that no substitution affected a CpG dinucleotide. We also report that advanced paternal age was observed among cohorts of sporadic NS cases with and without PTPN11 mutations and that a significant sex-ratio bias favoring transmission to males was present in subjects with sporadic NS caused by PTPN11 mutations, as well as in families inheriting the disorder.
authors.affiliation: Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanita, Rome, Italy. mtartaglia@iss.it
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Viviana
authors.initials: V
authors.lastname: Cordeddu
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Adam
authors.initials: A
authors.lastname: Shaw
authors.forename: Kamini
authors.initials: K
authors.lastname: Kalidas
authors.forename: Andrew
authors.initials: A
authors.lastname: Crosby
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patton
authors.forename: Mariella
authors.initials: M
authors.lastname: Sorcini
authors.forename: Ineke
authors.initials: I
authors.lastname: van der Burgt
authors.forename: Steve
authors.initials: S
authors.lastname: Jeffery
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
mesh_terms: D018899:CpG Islands; D004252:DNA Mutational Analysis; D005091:Exons; D019066:Facies; D005220:Fathers; D005260:Female; D005799:Genes, Dominant; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012737:Sex Factors; D012744:Sex Ratio
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases