Genetic heterogeneity in Noonan syndrome: Evidence for an autosomal recessive form

Burgt, C.J.A.M. van der; Brunner, Han G.

doi:10.1002/1096-8628(20000904)94:1<46::aid-ajmg10>3.0.co;2-i

Cited by 67 publications

(29 citation statements)

References 16 publications

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“…Indeed, the locus heterogeneity of Noonan syndrome has been indicated by a linkage analysis of a family of Noonan syndrome who did not show linkage to the 12q24 critical region (4). Clinically well-documented cases of Noonan syndrome who were born to consanguineous parents (22,23) also support the existence of an autosomal recessive, rather than autosomal dominant, form of Noonan syndrome. Furthermore, documentation of the Noonan syndrome phenotype in patients with t(5;7)(p15;q22) (24), t(3;22)(p21;q13), Nucleotide substitution A182G A188G A188G G214T C218T T854C A922G Exon 3 3 3 3 3 8 8 Amino acid substitution Asp61Gly Tyr63Cys Tyr63Cys Ala72Ser Thr73Ile Phe285Ser Asn308Asp…”

Section: Discussionmentioning

confidence: 99%

PTPN11(Protein-Tyrosine Phosphatase, Nonreceptor-Type 11) Mutations in Seven Japanese Patients with Noonan Syndrome

Kosaki

Suzuki

Muroya

et al. 2002

The Journal of Clinical Endocrinology & Metabolism

102

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Noonan syndrome is an autosomal dominant disorder defined by short stature, delayed puberty, and characteristic dysmorphic features. Tartaglia et al. (Nature Genetics, 29:465-468) have recently shown that gain-of-function mutations in the gene PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) cause Noonan syndrome in roughly half of patients that they examined. To further explore the relevance of PTPN11 mutations to the pathogenesis of Noonan syndrome, we analyzed the PTPN11 gene in 21 Japanese patients. Mutation analysis of the 15 coding exons and their flanking introns by denaturing HPLC and direct sequencing revealed six different heterozygous missense mutations (Asp61Gly, Tyr63Cys, Ala72Ser, Thr73Ile, Phe285Ser, and Asn308Asp) in seven cases (six sporadic and one familial). The mutations clustered either in the N-Src homology 2 domain or in the protein-tyrosine phosphatase domain. The clinical features of the mutation-positive and mutation-negative patients were comparable. The results provide further support to the notion that PTPN11 mutations are responsible for the development of Noonan syndrome in a substantial fraction of patients and that relatively infrequent features of Noonan syndrome, such as sensory deafness and bleeding diathesis, can also result from mutations of PTPN11.

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Section: Discussionmentioning

confidence: 99%

PTPN11(Protein-Tyrosine Phosphatase, Nonreceptor-Type 11) Mutations in Seven Japanese Patients with Noonan Syndrome

Kosaki

Suzuki

Muroya

et al. 2002

The Journal of Clinical Endocrinology & Metabolism

102

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“…Genetic heterogeneity has also been shown by lack of linkage to 12q24 of several smaller nuclear families. 4 PTPN11 encodes the nonreceptor protein tyrosine phosphatase SHP-2, an enzyme participating in several signal transduction cascades downstream of receptors for growth factors, cytokines and hormones. 5 The crystal structure of SHP-2 revealed an auto-inhibitory mechanism of the catalytic activity by the N-terminal SH-2 domain.…”

Section: Introductionmentioning

confidence: 99%

PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning

et al. 2003

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Noonan syndrome (NS, MIM 163950) is an autosomal dominant condition characterised by facial dysmorphy, congenital cardiac defects and short stature. Recently missense mutations in PTPN11, the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2 on 12q24, were identified in 50% of analysed Noonan cases. A large four-generation Belgian family with NS and some features suggestive of cardio-facio-cutaneous syndrome (CFC) was previously used to fine map the Noonan syndrome candidate region to a 5 cM region in 12q24. We now report the identification of a mutation (Gln79Arg) in the PTPN11 gene in this large family. In D. melanogaster and C. elegans the PTPN11 gene has been implicated in oogenesis. In this family two affected females had dizygous twins. This suggests that PTPN11 might also be involved in oogenesis and twinning in humans.

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“…Although autosomal dominance is common, autosomal recessive types have been described (Trauffer et al, 1994;van der Burgt and Brunner, 2000). Some family trees appear to support x-linked inheritance with maternal transmission being more frequent than paternal, due possibly to cryptorchidism in the male.…”

Section: Discussionmentioning

confidence: 99%