GM08747

GM08747 Fibroblast

Description:

IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME
DNA METHYLTRANSFERASE 3B; DNMT3B

Affected:

Yes

Sex:

Female

Age:

1 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Chromosome Abnormalities

Class

Syndromes with Increased Chromosome Breakage

Cell Type

Fibroblast

Transformant

Untransformed

Race

White

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Instability of heterochromatin of chromosomes #1, #9, and #16 with variable combined immunodeficiency; dysmorphic facial features, developmental delay, malabsorption, and recurrent infections; see GM08714 Lymphoid; 46,XX in fibroblasts; donor subject is a compound heterozygote: one allele has a G>A transition at nucleotide 1807 (1807G>A) of the DNMT3B gene resulting in an Ala to Thr substitution at codon 603 [Ala603Thr (A603T)], the mutation occurring in a region between motifs I and IV within the catalytic domain of DNMT3B; the second allele has a G>A transition within intron 22 located 11 nucleotides 5-prime of the normal splice acceptor site [IVS22AS,G>A,-11] resulting in the generation of a novel splice acceptor site and a 9-bp insertion in the processed RNA. This results in the insertion of 3 amino acids (serine, threonine, and proline) at codon 744 (744ins3). The insertion was within the conserved region of the catalytic domain, which is likely to be disrupted by the insertion of a proline residue. This mutation was de novo.

Characterizations

PDL at Freeze

6.89

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis and by Chromosome Analysis

Gene

DNMT3B

Chromosomal Location

20q11.2

Allelic Variant 1

602900.0008; ICF SYNDROME

Identified Mutation

ALA603THR; In a patient with ICF syndrome (242860), Okano et al. (1999) found compound heterozygosity for 2 mutations in the DNMT3B gene. The first was a G-to-A transition at nucleotide 1807, resulting in an ala603-to-thr substitution; this change was present in the proband and her mother. The mutation occurred in a region between motifs I and IV, within the catalytic domain of DNMT3B. The second heterozygous mutation was a G-to-A transition within intron 22, located 11 nucleotides 5-prime of the normal splice acceptor site (602900.0009). This mutation resulted in the generation of a novel splice acceptor site and a 9-bp insertion in the processed RNA, encoding 3 amino acids (serine, threonine, and proline) at codon 744. The insertion was within the conserved region of the catalytic domain, which is likely to be disrupted by the insertion of a proline residue. This mutation was de novo.

Gene

DNMT3B

Chromosomal Location

20q11.2

Allelic Variant 2

602900.0009; ICF SYNDROME

Identified Mutation

IVS22AS,G>A,-11; In a patient with ICF syndrome (242860), Okano et al. (1999) found compound heterozygosity for 2 mutations in the DNMT3B gene. The first was a G-to-A transition at nucleotide 1807, resulting in an ala603-to-thr substitution; this change was present in the proband and her mother. The mutation occurred in a region between motifs I and IV, within the catalytic domain of DNMT3B. The second heterozygous mutation was a G-to-A transition within intron 22, located 11 nucleotides 5-prime of the normal splice acceptor site (602900.0009). This mutation resulted in the generation of a novel splice acceptor site and a 9-bp insertion in the processed RNA, encoding 3 amino acids (serine, threonine, and proline) at codon 744. The insertion was within the conserved region of the catalytic domain, which is likely to be disrupted by the insertion of a proline residue. This mutation was de novo.

Phenotypic Data

Remarks

Publications

Yehezkel S, Segev Y, Viegas-Péquignot E, Skorecki K, Selig S, Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions Human molecular genetics: 2008

PubMed ID: 18558631

Weisenberger DJ, Velicescu M, Cheng JC, Gonzales FA, Liang G, Jones PA, Role of the DNA methyltransferase variant DNMT3b3 in DNA methylation. Mol Cancer Res2(1):62-72 2004

PubMed ID: 14757847

Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM, The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A96:14412-7 1999

PubMed ID: 10588719

Okano M, Bell DW, Haber DA, Li E, DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell99(3):247-57 1999

PubMed ID: 10555141