Description:
MENTAL RETARDATION, AUTOSOMAL RECESSIVE 34; MRT34
CASP2 AND RIPK1 DOMAIN-CONTAINING ADAPTOR WITH DEATH DOMAIN; CRADD
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases
PIGI Consented Sample |
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Cell Type
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Fibroblast
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Tissue Type
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Skin
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Transformant
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Untransformed
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Race
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White
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Ethnicity
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Not Hispanic/Latino
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Ethnicity
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Old Order Mennonite
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Country of Origin
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USA
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Family Member
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1
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Family History
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Y
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Relation to Proband
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proband
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Confirmation
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Molecular characterization before cell line submission to CCR
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| PDL at Freeze |
4.49 |
| Passage Frozen |
2 |
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by LINE assay |
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| Gene |
CRADD |
| Chromosomal Location |
12q22 |
| Allelic Variant 1 |
603454.p.Gly128Ar; MENTAL RETARDATION, AUTOSOMAL RECESSIVE 34 |
| Identified Mutation |
c.382G>C; In 5 Mennonite patients with autosomal recessive nonsyndromic mental retardation-34 (MRT34; 614499), Puffenberger et al. (2012) identified a homozygous 382G-C transversion in the CRADD gene, resulting in a gly128-to-arg (G128R) substitution in a highly conserved residue in the CRADD death domain. The mutation was found by homozygosity mapping followed by exome sequencing. Seven heterozygous carriers of this mutation were found among 203 Mennonite control samples, yielding a population-specific allele frequency of 1.72%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.) Overexpression of mutant murine Cradd with the G128R mutation showed normal protein localization to the nucleus and cytoplasm. However, when co-overexpressed with wildtype Pidd (605247), mutant G128R Cradd formed large cytoplasmic aggregates with a relative loss of Cradd expression in the nucleus. The findings suggested that the G128R mutation alters 1 of the interaction surfaces of the CRADD death domain to decrease affinity for the PIDD death domain. |
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| Gene |
CRADD |
| Chromosomal Location |
12q22 |
| Allelic Variant 2 |
603454.p.Gly128Ar; MENTAL RETARDATION, AUTOSOMAL RECESSIVE 34 |
| Identified Mutation |
c.382G>C; In 5 Mennonite patients with autosomal recessive nonsyndromic mental retardation-34 (MRT34; 614499), Puffenberger et al. (2012) identified a homozygous 382G-C transversion in the CRADD gene, resulting in a gly128-to-arg (G128R) substitution in a highly conserved residue in the CRADD death domain. The mutation was found by homozygosity mapping followed by exome sequencing. Seven heterozygous carriers of this mutation were found among 203 Mennonite control samples, yielding a population-specific allele frequency of 1.72%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.) Overexpression of mutant murine Cradd with the G128R mutation showed normal protein localization to the nucleus and cytoplasm. However, when co-overexpressed with wildtype Pidd (605247), mutant G128R Cradd formed large cytoplasmic aggregates with a relative loss of Cradd expression in the nucleus. The findings suggested that the G128R mutation alters 1 of the interaction surfaces of the CRADD death domain to decrease affinity for the PIDD death domain. |
| Remarks |
Clinically affected; relative macrocephaly: OFC 65th percentile for age, 7th percentile for height and weight; moderate intellectual disability; normal development until age 2 years when speech and language delays became more apparent; spoke single words at 3 years of age; spoke sentences of two or more years at 4-5 years of age; impulsive, inattentive, and distractible behavior: lacks stranger anxiety and generally exhibits impulsive and disinhibited behavior; pachygyria diagnosed by MRI at age 2 years: thickened cortical gray matter of the frontal, parietal, and temporal lobes, with a distinct gray-white margin and simplified gyral pattern; brief episodes of blank staring and eye fluttering noted and diagnosed as epilepsy; EEG performed at age 4 years showed multiple brief bilateral polyspike and spike-wave discharges; staring episodes continued on a regular basis but are well-controlled with medication; whole exome sequencing revealed a homozygous autosomal recessive mutation c.382G>C (p.Gly128Arg) in the CRADD gene; GM25981 is the unaffected carrier mother; has affected sister (not in catalog). |
| Cumulative PDL at Freeze |
4.49 |
| Passage Frozen |
2 |
| Split Ratio |
1:5 |
| Temperature |
37 C |
| Percent CO2 |
5% |
| Percent O2 |
3% |
| Medium |
Eagles Minimum Essential Medium with Earle's salts:Dulbecco's modified MEM with 2mM L-glutamine or equivalent |
| Serum |
15% fetal bovine serum Not inactivated |
| Supplement |
- |
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