NA25978
DNA from Fibroblast
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 |
| Quantity |
10 µg |
| Quantitation Method |
Please see our FAQ |
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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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Sample Source
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DNA from Fibroblast
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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 |
5.17 |
| 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; macrocephaly: OFC>99th percentile for age, but no dysmorphic features; moderate intellectual disability: gross and fine motor skills on target; language delay: first word spoken at 18 months; no behavioral phenotype, however sometimes easily distracted, has difficulty sustaining attention; learning disability noted in first grade, with ongoing overall delay in cognitive, adaptive, and social development; no history of seizures, however brain MRI at age 13 years showed pachygyria; whole exome sequencing confirmed by Sanger sequencing revealed a homozygous mutation c.382G>C (p.Gly128Arg) in the CRADD gene; mother (unaffected carrier) is GM25977; paternal grandfather (unaffected carrier) is GM25979. |
| Puffenberger EG, Jinks RN, Sougnez C, Cibulskis K, Willert RA, Achilly NP, Cassidy RP, Fiorentini CJ, Heiken KF, Lawrence JJ, Mahoney MH, Miller CJ, Nair DT, Politi KA, Worcester KN, Setton RA, Dipiazza R, Sherman EA, Eastman JT, Francklyn C, Robey-Bond S, Rider NL, Gabriel S, Morton DH, Strauss KA, Genetic mapping and exome sequencing identify variants associated with five novel diseases PloS one7:e28936 2011 |
| PubMed ID: 22279524 |
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