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Mucolipidosis IV

, MD, MHSc, , PhD, and , PhD.

Author Information
, MD, MHSc
Director, Institute of Metabolic Disease
Baylor Research Institute
Dallas, Texas
, PhD
MGH Center for Human Genetic Research / Harvard Medical School
Boston, Massachusetts
, PhD
Section on Molecular Neurogenetics
Medical Genetics Branch
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: July 30, 2015.

Summary

Clinical characteristics.

Mucolipidosis IV is characterized by severe psychomotor delay evident by the end of the first year of life and slowly progressive visual impairment during the first decade as a result of a combination of corneal clouding and retinal degeneration. By the end of the first decade of life and certainly by their early teens, all individuals with typical mucolipidosis IV have severe visual impairment as a result of retinal degeneration. Neurodegeneration is thought to occur in no more than 15% of individuals. About 5% of individuals have atypical mucolipidosis IV, often manifest as less severe psychomotor retardation and/or eye findings. Although in the past, mucolipidosis IV was considered an Ashkenazi Jewish disease, currently most affected individuals are non-Ashkenazi Jewish.

Diagnosis/testing.

Mucolipidosis IV is suspected in individuals with typical clinical findings and elevated plasma gastrin concentration or polymorphic lysosomal inclusions in skin or conjunctival biopsy. Identification of biallelic pathogenic variants in MCOLN1 confirms the diagnosis. The two variants, c.406-2A>G and 6.4 kb del (also known as g.511_6943del), account for 95% of pathogenic variants in individuals of Ashkenazi Jewish heritage.

Management.

Treatment of manifestations: Speech therapy; physical therapy for spasticity and ataxia; ankle-foot orthotics (AFOs) as needed; antiepileptic drugs as needed; topical lubricating eye drops, artificial tears, gels, or ointments for ocular irritation; surgical correction of strabismus; high-contrast black and white materials for those with visual impairment.

Prevention of secondary complications: Physical therapy to prevent permanent joint contractures; oral iron to prevent iron deficiency anemia from poor absorption of dietary iron.

Genetic counseling.

Mucolipidosis IV is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for families in which both MCOLN1 pathogenic variants have been identified.

Diagnosis

Suggestive Findings

Mucolipidosis IV should be suspected in any individual with the following clinical and laboratory findings.

Clinical findings

  • Early onset of developmental delay whether static, as in cerebral palsy, or progressively declining with loss of previously acquired cognitive and motor abilities [Altarescu et al 2002]
  • Dystrophic retinopathy with or without corneal clouding [Smith et al 2002]

Laboratory findings. Plasma gastrin concentration is elevated in virtually all individuals with mucolipidosis IV (mean 1507 pg/mL; range 400-4100 pg/mL) (normal 0-200 pg/mL) [Schiffmann et al 1998, Altarescu et al 2002].

Establishing the Diagnosis

The diagnosis of mucolipidosis IV is established in a proband with biallelic pathogenic variants in MCOLN1 (see Table 1) or (if molecular genetic testing is unavailable and/or uninformative) identification of characteristic inclusions on skin biopsy or conjunctival swab.

Molecular Genetic Testing

Approaches can include single-gene testing, use of a multi-gene panel, and genomic testing.

Single-gene testing. Sequence analysis of MCOLN1 is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.

In individuals of Ashkenazi Jewish ancestry targeted analysis for the two common pathogenic variants – c.406-2A>G and a 6.4-kb deletion beginning in the 5’UTR and extending into exon 6 – can be performed first, as they account for 95% of pathogenic variants in this population. An estimated 70% of individuals with mucolipidosis IV are of Ashkenazi Jewish heritage [Altarescu et al 2002].

Note: The common 6.4-kb deletion cannot be detected by routine sequencing. Other methods such as gene-targeted deletion/duplication analysis or a genotyping assay specifically designed to detect this deletion (e.g., breakpoint PCR or allele-specific primer extension) must be employed.

A multi-gene panel that includes MCOLN1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.

Genomic testing may be considered if serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of mucolipidosis IV. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

For issues to consider in interpretation of genomic test results, click here.

Table 1.

Summary of Molecular Genetic Testing Used in Mucolipidosis IV

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
Ashkenazi JewishNon-Ashkenazi Jewish
MCOLN1Targeted analysis for pathogenic variants 395%6%-10%
Sequence analysis 4, 577%-81%99%
Gene-targeted deletion/duplication analysis 6, 718% / unknown 8Unknown 8
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

For the pathogenic variants c.406-2A>G (77%) and 6.4 kb del (18%). Note: Reported breakpoints for this deletion vary slightly; see HGMD.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Cannot detect 6.4 kb del, one the two pathogenic variants common in persons of Ashkenazi Jewish heritage

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Required to detect the common 6.4-kb deletion observed in persons of Ashkenazi Jewish heritage and other novel (multi)exon deletions. Note that other genotyping assays specifically designed to detect the 6.4-kb deletion (e.g., breakpoint PCR or allele-specific primer extension) may be employed.

8.

No data on detection rate of non-6.4-kb deletion gene-targeted deletion/duplication analysis are available.

Biopsy

In the past, identification of abnormal lamellar membrane structures and amorphous cytoplasmic inclusions in diverse cell types on skin biopsy was used to confirm the diagnosis of mucolipidosis IV [Bargal et al 2002]. Subsequently, demonstration of typical vacuolation by PAS staining of conjunctival cells obtained with a swab was used for diagnosis [Smith et al 2002].

Clinical Characteristics

Clinical Description

Mucolipidosis IV is a neurodevelopmental disorder that is also neurodegenerative in about 15% of individuals. The phenotype in affected individuals can be either typical (~95% of individuals) or atypical (~5% of individuals) [Altarescu et al 2002]. Although individuals with mucolipidosis IV generally survive to adulthood, life expectancy is reduced compared to healthy individuals.

Typical Mucolipidosis IV

The most common presentation is severe psychomotor delay by the end of the first year of life in a child who is subsequently noted to have visual impairment caused by a combination of corneal clouding and retinal degeneration.

Neurologic findings. Psychomotor development is usually limited to few or no words and poor hand use [Altarescu et al 2002]; some may develop the ability to sit independently or crawl. Most individuals do not achieve independent walking [Altarescu et al 2002]; a few have learned to walk with the aid of a walker [Altarescu et al 2002].

Receptive language is better than expressive language; some individuals have used up to 50 signs to communicate.

Neurologic examination typically reveals severe dysarthria or anarthria, slow chewing, slow eating and swallowing, and spastic diplegia or quadriplegia [Altarescu et al 2002]. Individuals may be hypotonic, but tendon reflexes are usually hyperactive.

Neurologic deficits generally remain static during the first three decades of life [Altarescu et al 2002]; however, some individuals have neurologic deterioration best observed by serial brain magnetic resonance imaging volumetry and diffusion weighted imaging [Schiffmann et al 2014].

Brain MRI typically shows hypoplasia of the corpus callosum with absent rostrum and a dysplastic or absent splenium, signal abnormalities in the white matter on T1-weighted images, and increased ferritin deposition in the thalamus and basal ganglia. Atrophy of the cerebellum is observed in older individuals [Frei et al 1998].

Epileptiform discharges on EEG are common but are infrequently associated with clinical seizures [Siegel et al 1998].

Eye findings. Individuals with typical mucolipidosis IV have superficial corneal clouding that is bilateral, symmetric, and most visible in the central cornea [Smith et al 2002]. The corneal opacification is limited to the epithelium without stromal involvement or edema [Authors, personal observation], early reports of stromal abnormalities notwithstanding. On occasion, corneal clouding is the feature that prompts medical evaluation.

Painful episodes consistent with corneal erosions are common, but appear to decrease in frequency and severity with age.

Vision may be close to normal at a young age. Over the first decade of life, progressive retinal degeneration with varying degrees of vascular attenuation, retinal pigment epithelial changes, and optic nerve pallor result in further decrease in vision [Siegel et al 1998, Altarescu et al 2002, Pradhan et al 2002, Smith et al 2002]. Bilateral bull's eye maculopathy was observed in one individual [Smith et al 2002]. Visual acuity is difficult to test in most individuals with mucolipidosis IV, but is decreased in almost all persons older than age five years. Virtually all individuals with mucolipidosis IV develop severe visual impairment by their early teens as a result of the retinal degeneration.

In rare instances, mucolipidosis IV may consist of isolated retinal dystrophy [Goldin et al 2008].

Other ocular findings are strabismus (>50% of individuals), nystagmus, ptosis, and cataract [Bach 2001, Smith et al 2002]. The pupillary response to light is usually sluggish without evidence of relative afferent pupillary defect [Smith et al 2002].

Renal findings. Progressive renal failure which has been recognized in recent years is now considered a feature of the classic form of mucolipidosis IV. It manifests itself in the third decade of life [Author, unpublished data]. Because of chronic muscle atrophy in mucolipidosis IV, blood cystatin c level is the most sensitive way to diagnose renal insufficiency.

Other. Iron deficiency occurs in about 50% of affected individuals, and iron deficiency anemia, which is usually well tolerated, occurs in about 10% of affected individuals [Altarescu et al 2002].

The achlorhydria is asymptomatic.

The face is not typically coarse but has typical features [Goldin et al 2014].

Affected individuals do not have hepatosplenomegaly or specific skeletal abnormalities.

Atypical and Mild Mucolipidosis IV

Individuals with atypical mucolipidosis IV are less severely affected than individuals with typical mucolipidosis IV or have one organ system disproportionately affected [Altarescu et al 2002].

Some individuals attain the ability to walk independently or have isolated dystrophic retinopathy without neurologic dysfunction [Goldin et al 2008]. They develop slowly progressive ataxia, have mild eye abnormalities, and are usually of non-Ashkenazi Jewish descent [Altarescu et al 2002].

Some present with a congenital myopathy with significant generalized hypotonia and elevated serum muscle creatine kinase (CK) concentration.

Some present with static (non-progressive) motor and cognitive delay and minimal ocular abnormalities.

  • One female who presented with progressive visual impairment with corneal clouding with the appearance of cornea verticillata, retinopathy, normal psychomotor development, and behavioral abnormalities developed unstable gait in her twenties [Altarescu et al 2002].
  • Two other individuals with no neurologic deficit were diagnosed based on ocular findings [Dobrovolny et al 2007, Goldin et al 2008]. These individuals had all the other typical features of mucolipidosis IV including achlorhydria and autofluorescent inclusions in cultured skin fibroblasts [Dobrovolny et al 2007, Goldin et al 2008].

Genotype-Phenotype Correlations

Individuals of Ashkenazi Jewish ancestry usually have the severe form of mucolipidosis IV.

A pathogenic variant that creates a new preferred splice site of MCOLN1, c.1406A>G (p.Phe454_Asn569del) was identified in a Canadian family from Newfoundland; it causes an atypical form of mucolipidosis IV, in which affected individuals walk independently and have better communicative skills [Altarescu et al 2002].

Variants in the loop between the first and second transmembrane domain. Pathogenic variants found in the loop between the first and second transmembrane domain, one in the lipase domain and one eliminating one of the four cysteines in the loop, possibly reduce the stability of mucolipin-1. Individuals with these pathogenic variants had a mild phenotype, an independent ataxic gait, and the ability to use their hands to feed themselves.

The typical, rather severe presentation associated with the c.694A>C (p.Thr232Pro) pathogenic variant in the same region may be explained by the fact that the abnormal protein does not reach the endocytic compartment and accumulates in the endoplasmic reticulum [Manzoni et al 2004].

Variants in the third transmembrane domain. In several individuals from the southeast United States, a c.1084G>T (p.Asp362Tyr) pathogenic variant was identified in the third transmembrane domain. This pathogenic variant was associated with a slower progression of the retinal disease and a relatively mild neurologic phenotype, although membrane preparations containing mucolipin-1 with this pathogenic variant had no channel activity [Raychowdhury et al 2004].

Variants in the fourth transmembrane domain. Several MCOLN1 pathogenic variants are in the fourth transmembrane domain, including c.1221_1223delCTT (p.Phe408del), which causes the mildest mucolipidosis IV phenotype known [Altarescu et al 2002].

Variants between the fifth and sixth transmembrane domain. Several other pathogenic variants are in the area encoding the presumed channel pore between the fifth and sixth transmembrane domain. Most of those were associated with a severe mucolipidosis IV phenotype (Table 3) [Altarescu et al 2002].

Nomenclature

Mucolipidosis IV was classified as a mucolipidosis because of the initial impression of simultaneous storage of lipids and water-soluble substances.

Prevalence

The combined carrier frequency of the two pathogenic variants common in persons of Ashkenazi Jewish descent ranges from 1:100 to 1:127 [Bargal et al 2001, Edelmann et al 2002]. Of note, in a small group of 123 individuals, other investigators found a higher frequency [Wang et al 2001].

Prior to the availability of molecular diagnosis of mucolipidosis IV, individuals with atypical mucolipidosis IV were thought to have cerebral palsy, suggesting that mucolipidosis IV is underdiagnosed.

Differential Diagnosis

Because of the relatively static nature of the neurologic abnormality in mucolipidosis IV, individuals considered to have "cerebral palsy" should be evaluated for mucolipidosis IV.

The neurologic abnormalities and the finding of widespread storage material in tissue biopsy could suggest other lysosomal storage disorders including mucolipidosis type I (OMIM 256550), mucolipidosis type II, and the mucopolysaccharidoses (MPS I, MPS II, MPS IVA, MPS IVB). See Mucopolysaccharidoses: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

The finding of white matter abnormalities and a thin dysplastic corpus callosum could suggest other inherited hypomyelinating leukodystrophies such as sialic acid storage disease (Salla disease). (See Free Sialic Acid Storage Disorders and Leukodystrophy Overview.)

Corneal clouding also occurs in:

Cornea verticillata (without retinal dystrophy) occurs in Fabry disease.

The retinal dystrophy of mucolipidosis IV is similar to that observed in the neuronal ceroid-lipofuscinoses and other genetic disorders with retinal degeneration such as Bardet-Biedl syndrome and Alström syndrome.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mucolipidosis IV, the following evaluations are recommended:

  • Ophthalmic examination
  • Brain MRI
  • Iron studies
  • Neurologic evaluation, including EEG
  • Consultation with a medical geneticist and/or genetic counselor

Treatment of Manifestations

The following treatment is appropriate:

  • Speech therapy
  • Physical therapy and rehabilitation for motor dysfunction (mainly spasticity and ataxia)
  • Ankle-foot orthotics in individuals with hypotonia and weakness of ankle dorsiflexion
  • Antiepileptic drugs
  • Topical lubricating eye drops, artificial tears, gels, or ointments for management of the intermittent ocular irritation seen frequently in younger children
  • Surgical correction of strabismus
  • High-contrast black and white materials for those with visual impairment

Note: Corneal transplantation has not been successful because the donor corneal epithelium is eventually replaced by the abnormal host epithelium.

Prevention of Secondary Complications

Physical therapy and rehabilitation can help prevent permanent joint contractures.

An iron preparation such as oral ferrous sulfate is indicated for treatment of iron deficiency anemia resulting from poor absorption of dietary iron.

Surveillance

Annual follow up with a generalist is appropriate.

Agents/Circumstances to Avoid

Chloroquine may be contraindicated, based on published research in patient cultured skin fibroblasts [Goldin et al 1999].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Mucolipidosis IV is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one MCOLN1 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with mucolipidosis IV do not reproduce. No information is available regarding the ability of individuals with mild disease to reproduce.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of an MCOLN1 pathogenic variant.

Heterozygote (Carrier) Detection

Carrier testing for at-risk relatives requires prior identification of the MCOLN1 pathogenic variants in the family.

Population Screening

Because of the high carrier rate in individuals of Ashkenazi Jewish descent and the availability of premarital, preconception, and prenatal genetic counseling as well as prenatal diagnosis, the two MCOLN1 pathogenic variants commonly seen in persons of Ashkenazi Jewish heritage are often included in the panel of "Ashkenazi Jewish mutations" offered to individuals interested in preconception or prenatal risk assessment modification. Through this type of screening, couples in which both partners are carriers can be made aware of their status and risks before having affected children. Through genetic counseling and the option of prenatal testing, such families can, if they choose, bring to term only those pregnancies in which the fetus is unaffected.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the MCOLN1 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the MCOLN1 pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Mucolipidosis IV Foundation
    3500 Piedmont Road
    Suite 500
    Atlanta GA 30305
    Phone: (877) ML4-5459 (654-5459)
    Email: www@ml4.org
  • My46 Trait Profile
  • National MPS Society
    PO Box 14686
    Durham NC 27709-4686
    Phone: 877-677-1001 (toll-free); 919-806-0101
    Fax: 919-806-2055
    Email: info@mpssociety.org
  • Society for Mucopolysaccharide Diseases (MPS)
    MPS House Repton Place
    White Lion Road
    Amersham Buckinghamshire HP7 9LP
    United Kingdom
    Phone: 0345 389 9901
    Email: mps@mpssociety.co.uk
  • Center for Jewish Genetics
    Ben Gurion Way
    30 South Wells Street
    Chicago IL 60606
    Phone: 312-357-4718
    Email: jewishgeneticsctr@juf.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Mucolipidosis IV: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
MCOLN119p13​.2Mucolipin-1MCOLN1 databaseMCOLN1

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Mucolipidosis IV (View All in OMIM)

252650MUCOLIPIDOSIS IV; ML4
605248MUCOLIPIN 1; MCOLN1

Molecular Genetic Pathogenesis

The lysosomal storage of lipids and water-soluble substances in mucolipidosis IV is attributed to a transport defect in the late steps of endocytosis resulting from abnormal membrane components of endosomes. Endosomes shuttle lipids and proteins between the plasma membrane and the various cellular organelles. Nutrients bound to lysosomes for processing would be retained in these transition vesicles. Alternatively it could indicate an increased rate of membrane recycling resulting from rapid degradation of malfunctioning protein complexes at the plasma membrane. Inability of cells to compensate for the missing cation channel function causes the defect in organization of white matter in the brain and reduces maintenance of cells in the retina and optic nerve. Inability to secrete gastric acid may be directly related to a defect in the operation of the acid-secreting H+K+ ATPase in stomach parietal cells.

In C. elegans a pathogenic variant in an ABC transporter gene compensates for mucolipin deficiency and leads to viable worms, indicating that loss of a regulatory effect of mucolipin on the activity of the transporter is probably the cause of death in mucolipin-deficient worms [Schaheen et al 2006].

Gene structure. MCOLN1 spans 12,300 base pairs and comprises 14 exons. In humans, no expressed splice variants are known. A single-nucleotide polymorphism, c.984C>T (p.Asn328Asn), results in no amino acid change (reference sequence NM_020533.1).

Pathogenic allelic variants. A variety of pathogenic variants cause mucolipidosis IV, including pathogenic splice variants, small and large deletions and insertions, and pathogenic nonsense and missense variants (Table 3).

The two most prevalent pathogenic variants cause the majority of mucolipidosis IV in the Ashkenazi Jewish population.

  • One is the splice variant c.406-2A>G, which prevents splicing of mucolipin-1 mRNA at exon 4, resulting in a mix of unstable aberrant mRNA species.
  • The second, 6.4 kb del (also known as g.511_6943del), is a deletion of 6434 bp of DNA, including exons 1 through 5 and part of exon 6 of MCOLN1. A Polish individual with a non-Jewish haplotype was found to be heterozygous for this pathogenic variant [Sun et al 2000].

Pathogenic missense variants were found in the loop between the first and second transmembrane domain, one in the lipase domain, and one eliminating the four cysteines in the loop, possibly reducing the stability of mucolipin. See Table 2 (pdf) for a summary of additional pathogenic variants not discussed in this review. For more information, see Table A.

The variant c.1221_1223delCTT (p.Phe408del), located in the fourth transmembrane domain, causes the mildest mucolipidosis IV phenotype known [Altarescu et al 2002]. In vitro the protein construct with this pathogenic variant still functions as a channel in liposome preparations and only displays a deficiency in regulation [Raychowdhury et al 2004]. Overexpressed Phe408del variant retains Fe2+ channel permeability as indicated by Patch-clamping of late-endosomal and lysosomal membrane [Dong et al 2008], possibly underlying the milder disease phenotype in this individual.

Table 3.

Selected MCOLN1 Pathogenic Variants

DNA Change
(Alias 1)
Protein ChangeReference Sequence
c.406-2A>G
(IVS3-2A>G)
NM_020533​.2
AF287270
6.4-kb deletion
(g.511_6943del)
Deletion of exons 1-5 and part of exon 6AF287270
c.694A>Cp.Thr232ProNM_020533​.2
c.1084G>Tp.Asp362Tyr
c.1221_1223delCTTp.Phe408del
c.1406A>G 2
(g.9107A>G)
p.Phe454_Asn569del
c.1704A>T 3See footnote 3
c.1615delG 4p.Ala539ProfsTer41 4

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Base pair transition creates a new preferred splice acceptor site that results in a frameshift.

3.

Near the donor site of intron 13; creates an alternative donor splice site that results in a frameshift [Dobrovolny et al 2007]

4.

Normal gene product. Mucolipin-1 is a 580-amino acid protein that is a member of the transient receptor potential (TRP) family. Proteins of this family are generally considered Ca2+ channels. Mucolipin-1 has a high homology to mucolipin-2 and mucolipin-3. It also shows homologies to polycystin-2, the product of PKD2, one of two genes associated with autosomal dominant polycystic kidney disease. Mucolipin-1 and polycystin-2 function as nonselective cation channels in heterologous expression systems [Fares & Greenwald 2001, LaPlante et al 2002, Slaugenhaupt 2002, Raychowdhury et al 2004, Treusch et al 2004].

Abnormal gene product. Most pathogenic variants are null alleles resulting in no gene product. When an abnormal gene product exists, it is a nonfunctional protein.

References

Literature Cited

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  6. 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 Genet. 2000;67:1110–20. [PMC free article: PMC1288553] [PubMed: 11013137]
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Chapter Notes

Author History

Ehud Goldin, PhD (2004-present)
Yulia Grishchuk, PhD (2015-present)
Raphael Schiffmann, MD, MHSc (2004-present)
Susan A Slaugenhaupt, PhD; Harvard Medical School (2004-2015)
Janine Smith, MD; National Institutes of Health (2004-2015)

Revision History

  • 30 July 2015 (me) Comprehensive update posted live
  • 20 July 2010 (me) Comprehensive update posted live
  • 6 June 2007 (me) Comprehensive update posted to live Web site
  • 1 December 2005 (rs) Revision: sequence analysis no longer clinically available
  • 28 January 2005 (me) Review posted to live Web site
  • 16 August 2004 (rs) Original submission
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