GM02533

GM02533 LCL from B-Lymphocyte

Description:

MUCOLIPIDOSIS IV
MUCOLIPIN 1; MCOLN1

Affected:

Yes

Sex:

Female

Age:

2 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Lysosomal Storage Diseases
GeT-RM Samples

Class

Disorders of Carbohydrate Metabolism

Alternate IDs

GM17360 [MUCOLIPIDOSIS IV]

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

White

Ethnicity

ASHKENAZI

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Ashkenazi; see GM02048 Fibroblast; affected sib is GM02529 Amniotic; photophobia; bilateral corneal opacities; abnormal lysosomal storage bodies; donor subject is a compound heterozygote: one allele has an A>G transition in the acceptor splice site of the third intron of the MCOLN1 gene (IVS3AS-2A>G) resulting in the skipping of exon 4; the second allele has a 6,450 bp deletion spanning a region from 928 bp upstream from the first exon to bp 31 of exon 7 (del ex1-ex7)

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

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

MUTATION VERIFICATION

The gene mutation(s) in this sample have been verified by 6 laboratories.

Gene

MCOLN1

Chromosomal Location

19p13.3-p13.2

Allelic Variant 1

605248.0001; MUCOLIPIDOSIS IV

Identified Mutation

IVS3AS,A>G,-2; In 12 of 21 Ashkenazi Jewish patients with mucolipidosis IV (252650) associated with the major Ashkenazi founder haplotype defined by Slaugenhaupt et al. (Am J Hum Genet 65:773-778, 1999), Bargal et al. (Nat Genet 26:118-121, 2000) identified a homozygous A-to-G transition in the acceptor splice site of the third intron of the MCOLN1 gene. One heterozygote was found among 60 Ashkenazi normal controls; this was consistent with the estimated frequency of heterozygotes (1/50) in this population. Bassi et al. (Am J Hum Genet 67:1110-1120, 2000) identified this acceptor splice site mutation, which they designated 486-2A-G, as the major founder mutation in Ashkenazi Jewish patients. The mutation disrupted the GT-AG rule of splicing and resulted in a transcript lacking 165 bp, because of the skipping of exon 4. This caused a frameshift leading to a premature translation termination 374 bp downstream. The predicted truncated protein retained only the first 21 amino acids of the wildtype protein.

Gene

MCOLN1

Chromosomal Location

19p13.3-p13.2

Allelic Variant 2

605248.0002; MUCOLIPIDOSIS IV

Identified Mutation

6,450-BP DEL; In 1 of 21 Ashkenazi Jewish patients with mucolipidosis IV (252650) associated with the minor founder haplotype defined by Slaugenhaupt et al. (Am J Hum Genet 65:773-778, 1999), Bargal et al. (Nat Genet 26:118-121, 2000) identified a homozygous 6,450-bp deletion in the MCOLN1 gene. The deletion spanned a region from 928 bp upstream from the first exon of MCOLN1 to bp 31 of exon 7 (del EX1-EX7).

Phenotypic Data

Remarks

Publications

La Cognata V, Cavallaro S, Detection of Structural Variants by NGS: Revealing Missing Alleles in Lysosomal Storage Diseases Biomedicines10: 2022

PubMed ID: 36009380

Kalman L, Wilson JA, Buller A, Dixon J, Edelmann L, Geller L, Highsmith WE, Holtegaard L, Kornreich R, Rohlfs EM, Payeur TL, Sellers T, Toji L, Muralidharan K, Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent The Journal of molecular diagnostics : JMD11:530-6 2009

PubMed ID: 19815695

Hantash FM, Olson SC, Anderson B, Buller A, Chen R, Crossly B, Sun W, Strom CM, Rapid one-step carrier detection assay of mucolipidosis IV mutations in the Ashkenazi Jewish population The Journal of molecular diagnostics : JMD8:282-7 2006

PubMed ID: 16645217

Bassi MT, Manzoni M, Monti E, Pizzo MT, Ballabio A, Borsani G, Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am J Hum Genet67(5):1110-20 2000

PubMed ID: 11013137

Kohn G, Livni N, Ornoy A, Sekeles E, Beyth Y, Legum C, Bach G, Cohen MM, Prenatal diagnosis of mucolipidosis IV by electron microscopy. J Pediatr90:62-6 1977

PubMed ID: 830895