A human compound heterozygote for two MLH1 missense mutations

Hackman, Peter; Tannergård, Pia; Osei-Mensa, Salome; Chen, Jindong; Kane, Michael F.; Kolodner, Richard D.; Lambert, Bo; Hellgren, Dennis; Lindblom, Annika

doi:10.1038/ng1097-135

Cited by 40 publications

(26 citation statements)

References 13 publications

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“…A final point to be considered in the evaluation of missense mutations is that their presence does not exclude the coexistence of a causative mutation on the same or on the second allele of hMLH1 or hMSH2 (Farrington et al 1998;Hackman et al 1997). In the light of these observations, the three patients with missense mutations, MSI-H cancers, and loss of one mismatch repair protein require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer

Ward

Meldrum

Williams

et al. 2002

Journal of Cancer Research and Clinical Oncology

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Section: Discussionmentioning

confidence: 99%

Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer

Ward

Meldrum

Williams

et al. 2002

Journal of Cancer Research and Clinical Oncology

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“…Other diagnostic possibilities are McCune-Albright syndrome, Watson syndrome, and ring chromosome syndromes [Landau and Krafchik, 1999]. Recently, multiple café-au-lait spots have been reported in children carrying mutations in both alleles of one of the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2, which are known to cause hereditary non-polyposis colorectal cancer (HNPCC) in heterozygotes [Hamilton et al, 1995;Hackman et al, 1997;Ricciardone et al, 1999;Wang et al, 1999;De Rosa et al, 2000;Trimbath et al, 2001;Vilkki et al, 2001;Whiteside et al, 2002;Agostini et al, 2003;Bougeard et al, 2003;Hegde et al, 2003;Wagner et al, 2003;De Vos et al, 2004;Gallinger et al, 2004;Menko et al, 2004;Raevaara et al, 2004]. In addition to café-au-lait spots, these children developed hematologic malignancies and/or a glioblastoma at an early age, and some developed gastrointestinal neoplasia.…”

Section: Introductionmentioning

confidence: 99%

Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6

Østergaard

Sunde

Okkels

2005

American J of Med Genetics Pt A

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We report on a nonconsanguineous family in which two siblings with cutaneous manifestations leading to a diagnosis of neurofibromatosis type 1 (NF1) developed CNS tumors at an early age. In addition, one of them developed a T-cell lymphoma. Neither parent had NF1. The mother was known to be heterozygous for a MSH6 mutation, and the father was found to be heterozygous for a different MSH6 mutation. Screening of MSH2, MLH1, MSH6, PMS1, PMS2, and MLH3 in the affected children disclosed that they both were compound heterozygote for the MSH6 mutations of their parents. Most recently, about a dozen other cases of inherited bi-allelic deficiency of mismatch repair (MMR) genes associated with early onset CNS tumors, hematologic malignancy, gastrointestinal neoplasia, café-au-lait spots, and other NF1 features have been reported. In the present study, we summarize the clinical findings of 27 individuals homozygous or compound heterozygous for an MMR gene mutation reported in the medical literature. We suggest that biparentally inherited mutations of one of the MMR genes should be considered in children with multiple café-au-lait spots who have early-onset CNS tumors, hematologic malignancies, or early onset gastrointestinal neoplasia.

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“…This can further complicate the interpretation of the findings. Rarely, a patient can also carry two MMR gene variations either in the same gene or in different genes (Hackman et al 1997;Ricciardone et al 1999;Wang et al 1999;Wu et al 1999Wu et al , 2001De Rosa et al 2000;Samowitz et al 2001;Vilkki et al 2001;Whiteside et al 2002;http://www.nfdht.nl). If the variations are different, without extensive segregation analyses, it may be impossible to decide whether both, only one, or none of them is pathogenic.…”

Section: Introductionmentioning

confidence: 99%

Two mismatch repair gene mutations found in a colon cancer patient – which one is pathogenic?

Kariola

Otway²,

Lönnqvist

et al. 2003

Hum Genet

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Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome. Germline mutations in five different mismatch repair (MMR) genes, MSH2, MSH6, MLH1, MLH3, and PMS2 are linked to HNPCC. Here, we describe two colon cancer families in which the index patients carry missense mutations in both MSH2 and MSH6. The MSH2 mutation, I145M, is the same in both families, whereas the MSH6 mutations are different (R1095H and L1354Q). The families do not fulfil the international criteria for HNPCC, one family comprising two and the other family four colon cancer patients, all in one generation, resembling a recessive rather than dominant inheritance characteristic of HNPCC. The tumors of the index patients showed microsatellite instability. Functional analysis was performed to determine which one of the mutations could primarily underlie the cancer susceptibility in the families. MSH2 and MSH6 are known to form a heterodimeric complex (MutSalpha) responsible for mismatch recognition. The interaction of each mutated protein with its wild-type partner and with its mutated partner present in the colon cancer patient, and the MMR function of the mutated MutSalpha complexes were determined. Since none of the three mutations affected the MSH2-MSH6 interaction or the function of MutSalpha in an in-vitro MMR assay, our results suggest that alone the mutations do not cause MMR deficiency typical of HNPCC. However, our results do not exclude the possible compound pathogenicity of the two mutations.

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A human compound heterozygote for two MLH1 missense mutations

Cited by 40 publications

References 13 publications

Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer

Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer

Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6

Two mismatch repair gene mutations found in a colon cancer patient – which one is pathogenic?

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