ClinGen Dosage Sensitivity Curation Page

PLP1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
21679407 Grossi (2011) performed molecular testing on 48 male patients from 38 unrelated families with a PLP1-related disorder. PLP1 whole gene duplications were identified in 24 of the unrelated patients by real time PCR amplification from genomic DNA . Intragenic PLP1 variants were found in the remaining 14 patients One nonsense ((p.Gln69X), 7 missense mutations, a deletion (c.1-329_c.1_c.4+324del657) involving the removal of 657-bp from the untranslated region, a microdeletion (c.554_564del11) which results in a frameshift (p.Gln185LeufsX15) that is predicted to introduce a premature stop codon 15 residues downstream, and a microduplication in exon 2 (c.134_140dup7) which is predicted to lead to a frameshift (p.Ile47IlefsX4) with premature truncation of the protein four amino acids downstream. The genomic deletion (c.1-329_c.1_c.4+324del657) was found to overlap 4 nucleotides of exon 1 (including the start codon ATG), the flanking upstream 329-bp untranslated region (5?UTR) and the downstream 324-bp intronic regions. Authors evaluated RNA processing by using real time PCR. RNA extracted from the fibroblasts indicated that the PLP transcript isoform was completely absent, whereas the DM20 transcript isoform was present at a reduced level,~50% as compared to healthy controls (data not shown).
1720927 Raskind (1991) evaluated the PLP1 gene in a four generation family with two living males affected with PMD. Southern blot analysis showed an absence of of signal for the pLP1.5 and pLP1.3 probes with digests of DNA from affected males. Unaffected males gave the expected band pattern. In addition, both upstream and downstream sequences of the PLP1 coding region were shown to be included in the deletion. However, the limits of the deletion have not been defined.
16416265 Combes (2006) used multiplex amplifiable probe amplification technique to screen the PLP1 gene and the GPM6B gene for intragenic rearrangements in patients with hypomyelinating leukodystrophy (HL) present either with well- delineated phenotypes as Pelizaeus?Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2) or with unspecific phenotypes. The study identified two partial deletions of the PLP1 gene in two classic PMD patients (205-1 and 738-1). For patient 205-1, the six 5? probes could not be detected, suggesting a deletion of the promoter, exon 1, and part of intron 1,that could lead to a complete absence of PLP/DM20 proteins . For patient 738-1, deletion was observed for the two 3? probes of PLP1 (exon 6 and 3?UTR),that could lead to truncated PLP/DM20 proteins (missing the fourth transmembrane domain and the carboxy terminal cytoplasmic extremity) and/or to absence of PLP/DM20 proteins due to a lack of 3?UTR and poly(A) tail .
12297985 Inoue (2002), studied three families with PLP1 gene deletions Family HOU542, Family HOU669, and Family PMD1, (NOTE: Family PMD1, is from the Raskind et al ,1991; PMID:1720927). Each male patient with PLP1 deletion had a mild form of PMD or a complicated form of spastic paraplegia type 2. Interphase FISH on all three families showed patients carried a deletion of the PLP1 gene. PCR analyses did not amplify PLP1 exonic sequences in any of the three male probands. Together with the normal karyotypes, authors suggest the three patents have a submicroscopic deletion of PLP1 but distinct deletion sizes however, they involved only two other genes Family HOU669 : the deletion in the patient appeared to be inherited from the patients healthy mother. The mother had a slightly skewed X-inaactivation (data not shown (active vs. inactive X chromosome 82:18) . The deletion size spans ?600 Kb Family HOU542: Southern blot analysis showed the deletion to be inherited from the mother. FISH suggested the PLP1 gene deletion was a result of an unbalanced translocation involving chromosome 19. The mother had a slightly skewed X-inaactivation (data not shown (active vs. inactive X chromosome 81:19) . The deletion size in HOU542 spans greater than or equal to 750 Kb. Family PMD1: The maternal carrier showed random X-inactivation. The rearrangement in this family appeared to be complex., evidence suggests that the family does not have a simple deletion
11093273 Cailloux (2000) investigated 52 PMD and 28 SPG2 families with no large duplications or deletions of the entire PLP1 gene by PCR amplification of the 7 coding regions and the splice sites. A total of 29 PMD and 4 SPG2 were identified with variants within the PLP1 gene. Twenty three missense variants, 3 deletion/insertions with frame shifts and 7 splice site variants were identified.
11071483 Woodward (1998) looked at 4 families (DH, NO, DB, ND) that included 5 males with a diagnosis of PMD. All mother were asymptomatic. The duplication sizes were ~500 kb for families DB and DH and ~800kb for families NO and ND

Haploinsufficiency phenotype comments:

Pathogenic variants including, loss of function variants, are associated with PLP1-related disorders, include a range of phenotypes from Pelizaeus-Merzbacher disease to spastic-paraplegia 2. Whole gene deletions account fewer than 2% of individuals with Pelizaeus-Merzbacher disease. Female carriers of PLP1-related disorders are generally normal neurologically, but may manifest mild to moderate signs of late onset disease.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for triplosensitivity phenotype
PubMed ID Description
15689360 Wolf (2005) performed targeted FISH using a PLP1 cosmid DNA probe and MLPA to determine copy number of the PLP1 gene in 5 males with a diagnosis of Pelizaeus?Merzbacher disease (PMD). Patient 1: FISH results for patient 1 and his mother suggested a copy number >2. The mother was shown to have 4 copies of the PLP1 gene by MLPA consistent with Patient 1 having a triplication of the PLP1 gene. Patient 2: FISH results were performed on the mother, maternal grandmother and patient 2. FISH was difficult to interpret but suggested more than 3 copies in the mother, grandmother and affected male. Authors also concluded that the MLPA dosage for patient 2 was higher than patient 1's mother and concluded that patient 2 likely has 5 copies of the PLP1 gene . Patient 3, 4 and 5: FISH showed two PLP1-related probe signals in patient 3 and three in his mother. FISH was not performed for patients 4 and 5. Three copies of the PLP1 gene was detected by MLPA in Patients 3, 4, and 5. All 7 exons of the PLP1 gene gave results of a triplication , whereas other X-linked loci (the paper does not highlight which loci) showed single copy and autosomal control probes showed two copies. In Patients 3, 4 and 5 no maternal testing was performed. Although this study does show additional copies of the PLP1 gene on all patients, the author did not discuss the overall duplication size in each patient.
10417279 Mimault (1999) studied 82 patients with sporadic Pelizaeus?Merzbacher disease (PMD) in order to determine the type of variants and origin of the PLP1 gene variants. Testing was performed by sequencing the entire coding regions of the gene and by multiplex PCR-based test by coamplify exon IV from the PLP gene and exon IV from the CFTR gene in order to determine PLP-gene copy number. Pathogenic variants were found in 63 patients (77%). PLP1 duplications were seen in 62% of patients and point mutations in coding or splice site regions of the gene were seen in 38%. It is unknown if the duplications noted are just the PLP1 gene or if the duplications include other genes. To determine origin of the variants detected, authors examined 56 of the 63 mothers available for testing. In the 22 point mutations, 68% of mothers were heterozygous for the variant, while among the 34 duplicated cases, 91% of mothers were carriers.
19376225 Regis (2009) looked at the PLP/DM20 expression profile in fibroblasts of three male PMD patients with a PLP1 gene duplication with unknown breakpoints. PLP1 gene dosage was detected by real time PCR using an amplicon located in exon 3 of the PLP1 gene and two flanking amplicons located in intron 1 of the PLP1 gene and an amplicon in the untranslated portion of exon 7. Each patient was found to carry two copies of the PLP1 gene. Expression studies were performed using cDNA from each patient and controls. Combined PLP/DM20 and selective DM20 expression were evaluated. PLP gene expression in patients showed more than 4 fold increase when compared to normal controls. Authors then focused on the contribution of the PLP and DM20 transcripts in the observed overexpression. Results showed a 2 fold increase in DM20 expression when compared to controls. In addition authors quantified the quantity of the DM20 transcript to the PLP1 gene overexpression, all three patients showed a decrease of DM20/(DM20+PLP) ratio compared to normal controls, indicating a shift in the balance between the PLP and DM20 transcripts suggesting a prominent contribution of the PLP transcript to the PLP1 gene overexpression detected in the patients. Authors conclude that PLP1 gene duplication seems to result both in overexpression and in a shift of the PLP/DM20 splicing balance in direction of the PLP isoform.
9634530 Woodward (1998) looked at 4 families (DH, NO, DB, ND) that included 5 males with a diagnosis of PMD. All mother were asymptomatic. The duplication sizes were ~500 kb for families DB and DH and ~800kb for families NO and ND

Triplosensitivity phenotype comment:

Whole gene duplications account for about ~70% of patients with Pelizaeus-Merzbacher disease. Duplications are typically tandem, but can also be insertional. Triplications and quintuplications have also been observed. Female carriers of duplications are less likely to have clinical manifestations and more likely to have favorably skewed X-inactivation. Although reported cases contain unknown duplication sizes and duplications involving more than just the PLP1 gene, functional studies show that PLP1 is the causative gene of Pelizaeus-Merzbacher disease. Because of this, the PLP1 gene dosage triplosensitivity score is a 3.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.