Mucolipidosis IV is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities. The lysosomal hydrolases in ML IV are normal, in contrast to most other storage diseases. The disorder results from a defect ... Mucolipidosis IV is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmologic abnormalities. The lysosomal hydrolases in ML IV are normal, in contrast to most other storage diseases. The disorder results from a defect in transport along the lysosomal pathway, affecting membrane sorting and/or late steps of endocytosis, which causes intracellular accumulation of lysosomal substrates. Over 80% of the patients in whom the diagnosis of ML IV has been made are Ashkenazi Jews, including severely affected and mildly affected patients (Chen et al., 1998).
Amir et al. (1987) noted that the diagnosis of ML IV could be made by electron microscopic demonstration of storage organelles typical of the mucolipidoses.
- Prenatal Diagnosis
Caimi et al. (1982) noted that ... Amir et al. (1987) noted that the diagnosis of ML IV could be made by electron microscopic demonstration of storage organelles typical of the mucolipidoses. - Prenatal Diagnosis Caimi et al. (1982) noted that prenatal diagnosis of ML IV is possible with transmission electron microscopy of amniocytes, showing characteristic inclusions. Ornoy et al. (1987) proposed transmission electron microscopy with demonstration of lamellar bodies in endothelial cells of the chorionic villi for the prenatal diagnosis of ML IV.
Berman et al. (1974) reported an Ashkenazi Jewish infant with congenital corneal clouding and abnormal systemic storage bodies. Lysosomal hydrolases were normal. The disorder was characterized as a mucolipidosis because electron microscopy showed lysosomal storage of lipids together ... Berman et al. (1974) reported an Ashkenazi Jewish infant with congenital corneal clouding and abnormal systemic storage bodies. Lysosomal hydrolases were normal. The disorder was characterized as a mucolipidosis because electron microscopy showed lysosomal storage of lipids together with water-soluble granulated substances. Merin et al. (1975) described a disorder, termed mucolipidosis IV, in 4 unrelated children of Ashkenazi extraction traced to southern Poland. There were 3 females and 1 male. The most prominent clinical feature was corneal clouding from birth or early infancy, which was the presenting symptom in 2 of 4, followed by psychomotor retardation apparent by the end of the first year of life. Skeletal dysplasia, facial dysmorphism, and hepatosplenomegaly were absent. Conjunctival biopsies showed 2 types of abnormal fibroblast inclusion bodies: single-membrane-limited cytoplasmic vacuoles containing both fibrillogranular material and membranous lamellae, and lamellar and concentric bodies resembling those of Tay-Sachs disease (272800). Electroretinogram (ERG) performed in 1 patient was subnormal. The disorder was characterized as a mucolipidosis because electron microscopy showed lysosomal storage of lipids together with water-soluble granulated substances. Tellez-Nagel et al. (1976) reported a 7-year-old Ashkenazi Jewish boy who showed developmental regression at age 8 months. Corneal, conjunctival, and cerebral biopsies showed lipid-like and mucopolysaccharide-like concentric membranous lamellar lysosomal inclusions which were reminiscent of those found in the gangliosidoses. In the brain, dense fluorescent inclusions resembled those in ceroid-lipofuscinosis (see, e.g., 256730). Total ganglioside content of the white matter was increased, but the pattern was normal. The findings were consistent with ML IV. Goutieres et al. (1979) described 5 cases of mucolipidosis IV in non-Jews. Four patients were in 2 sibships. Crandall et al. (1982) reported a 2-year-old Ashkenazi Jewish girl who presented with developmental delay and microcephaly. Photophobia and corneal haze were noted at 9 months of age, and fibrous dysplasia and corneal opacities were found at 18 months. At 2 years, she had esotropia, mild coarse facies, and hypotonia, and was unable to walk or speak. Examination at 5 years showed neurologic progression of the disorder, with hoarse cry, nystagmus, truncal titubation, spasticity, dystonic posturing, hyperreflexia, and extensor plantar responses. She was unable to sit without support and did not respond to visual stimuli. There was no organomegaly, and urine analysis showed no oligosaccharide or mucopolysaccharide excretion. Electron microscopy showed cytoplasmic granular inclusions and concentric lamellar structures in liver, muscle, and nerve. Phospholipids were increased in liver, skin fibroblasts, and urine. Caimi et al. (1982) reported a 22-year-old Italian woman with cloudy corneae, capsular lens opacities, and severe and progressive mental and motor deterioration. Ultrastructural skin biopsy showed membranous cytoplasmic bodies in Schwann cells, vessel walls, fibroblasts, smooth muscle fibers, and sweat glands. There was a complete deficiency of ganglioside sialidase. Urine analysis showed accumulation of all phospholipid species, of several glycolipids, and of gangliosides. Caimi et al. (1982) suggested that ML IV could be called sialolipidosis to distinguish it from sialidosis (256550), in which the sialidase (neuraminidase) for glycoprotein and water-soluble oligosaccharides is deficient. They noted that ML IV heterozygotes show partial deficiency of ganglioside sialidase. Riedel et al. (1985) stated that 17 cases of ML IV had been reported; about half of them had Ashkenazi ancestry. Amir et al. (1987) reported heterogeneity in ophthalmologic features in 20 ML IV patients ranging in age from 2 to 17 years, noting differences in age at onset and in degree and clinical course of corneal opacities and retinal involvement. One patient, aged 5, had no corneal opacity although her vision was greatly reduced because of severe myopia and retinal degeneration. On the other hand, corneal opacities were congenital in 11 of the 20 cases. All patients had psychomotor retardation and visual impairment during the first year of life. The maximal developmental level achieved was 12 to 15 months. Chitayat et al. (1991) reported 5 patients with ML IV from 3 Ashkenazi Jewish families. The presenting symptoms were hypotonia, developmental delay, corneal clouding, and puffy eyelids. Four of the patients had convergent strabismus. None progressed beyond the developmental age of 15 months. In 1 patient, death was due to aspiration at age 17 years; the oldest patient entered puberty at 20 years, developed a coarse face at 30 years, and was 32 years old at the time of report. Bargal and Bach (1997) observed that even more severely affected ML IV patients, despite an early age at onset, showed very slow or hardly any deterioration in the clinical picture for the first 2 to 3 decades of life. In 14 of 15 ML IV patients, Frei et al. (1998) found a hypoplastic corpus callosum with absent rostrum and a dysplastic or absent splenium, dysmyelinating white matter abnormalities, and increased ferritin deposits in the thalamus and basal ganglia. Atrophy of the cerebellum and cerebrum was observed in older patients, reflecting disease progression. Pradhan et al. (2002) presented the progression of ERG findings in 2 patients with mucolipidosis IV. Both patients showed greater loss of b-wave than a-wave responses. In both, rod-mediated responses were minimal, cone-mediated responses were severely subnormal, and cone b-wave implicit times were prolonged. The electronegative ERG configuration suggested that the primary retinal disturbance in mucolipidosis IV might occur at or proximal to the photoreceptor terminals. The patient reported by Goldin et al. (2004) was 4 years old at the time of study and a Canadian of English and Scottish origin. She exhibited developmental delay, hypotonia, ataxia, central corneal clouding, and mild photophobia as a relatively moderate phenotype. No organomegaly was present. She walked only with a walker. She was without speech but used about 20 signs to communicate with her parents. She also was able to feed herself with her fingers. Skin biopsy showed membrane-bound osmiophilic lysosomal inclusions. She was compound heterozygous for 2 mutations in the MCOLN1 gene only 1 of which, inherited from the father, was expressed (see 605248.0007). Dobrovolny et al. (2007) reported an usually mild case of ML IV. The patient was a girl, not of Ashkenazi Jewish origin, who developed corneal cloudiness at age 2 years. She later developed progressive decreased visual acuity, corneal abrasions, and strabismus. At age 12 years, she showed retinal pigment abnormalities in the macula and retinal vessel attenuation. VEP and ERP examinations were consistent with bilateral retinal dystrophy. Ultrastructural examination showed storage lysosomes filled with either concentric membranes or lucent precipitate in corneal and conjunctival epithelia and vascular endothelium. There was also evidence of gastric parietal cell involvement leading to a compensatory increase in gastrin production. Otherwise, the patient had normal psychomotor development and no neurologic abnormalities. Genetic analysis identified compound heterozygosity for 2 mutations in the MCOLN1 gene (605248.0005; 605248.0009).
In 21 Ashkenazi Jewish ML IV patients, Bargal et al. (2000) identified 2 mutations in the MCOLN1 gene (605248.0001; 605248.0002) in correlation with the major and minor haplotypes identified by Slaugenhaupt et al. (1999). Six patients were compound ... In 21 Ashkenazi Jewish ML IV patients, Bargal et al. (2000) identified 2 mutations in the MCOLN1 gene (605248.0001; 605248.0002) in correlation with the major and minor haplotypes identified by Slaugenhaupt et al. (1999). Six patients were compound heterozygous for both mutations and 2 patients were compound heterozygous for 1 of the founder mutations and a second unidentified mutation. The clinical manifestations of all the patients showed similar severity. Sun et al. (2000) identified mutations in the MCOLN1 gene (605248.0004-605248.0006) in patients with ML IV. Goldin et al. (2004) identified 2 mutations in a 4-year-old girl with ML IV (605248.0007; 605248.0008).
Raas-Rothschild et al. (1999) interviewed 17 Israeli Ashkenazi families with ML IV patients to study their family origin. Although the families immigrated to Israel from various European countries, they could all trace their roots 3 to 4 generations ... Raas-Rothschild et al. (1999) interviewed 17 Israeli Ashkenazi families with ML IV patients to study their family origin. Although the families immigrated to Israel from various European countries, they could all trace their roots 3 to 4 generations back to northern Poland or the immediate neighboring country, Lithuania. Furthermore, there are only 1 or 2 ultraorthodox families among the 70 to 80 Ashkenazi families with ML IV patients worldwide, a marked underrepresentation of this group, which constitutes at least 10% of the Ashkenazi population. These data indicated that the ML IV mutation occurred only around the 18th or 19th century after the major expansion of this population, in a founder in this defined European region belonging to a modern, secular family.
Mucolipidosis IV should be suspected in any individual with the following:...
DiagnosisClinical DiagnosisMucolipidosis IV should be suspected in any individual with the following: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] TestingPlasma 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]. Biopsy of skin or conjunctiva shows accumulation of abnormal lamellar membrane structures and amorphous cytoplasmic inclusions in diverse cell types. Note: In the past, these findings were used to confirm the diagnosis of mucolipidosis IV [Bargal et al 2002]; more recently, however, demonstration of typical vacuolation by PAS staining of conjunctival cells obtained with a swab has been used for diagnosis [Smith et al 2002]. Molecular Genetic TestingGene. MCOLN1 is the only gene known to be associated with mucolipidosis IV. Clinical testing Targeted mutation analysis. An estimated 70% of individuals with mucolipidosis IV are of Ashkenazi Jewish heritage [Altarescu et al 2002]. Two mutations, c.406-2A>G and g.511_6943del, account for 95% of mutations in individuals of Ashkenazi Jewish heritage.Approximately 60% of individuals with mucolipidosis IV of Ashkenazi Jewish heritage in the US are homozygotes for the c.406-2A>G intronic acceptor splice-site mutation. An estimated 33% are compound heterozygotes for the two common mutations [Wang et al 2001, Goldin et al 2004]. Only one individual homozygous for the g.511_6943del mutation has been identified [Bargal et al 2000, Bassi et al 2000, Sun et al 2000]. Sequence analysis detects mutations in the remaining 5% of individuals of Ashkenazi Jewish heritage and about 99% of individuals of non-Ashkenazi Jewish heritage.Deletion/duplication analysis detects the common 6.4-kb deletion (g.511_6943del) and other novel exonic/multiexonic deletions. No additional information regarding the mutation detection frequency is currently available.Table 1. Summary of Molecular Genetic Testing Used in Mucolipidosis IVView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAshkenazi JewishNon-Ashkenazi JewishMCOLN1Targeted mutation analysisc.406-2A>G, g.511_6943del 295%6%-10%Clinical Sequence analysisSequence variants 3, 499%399%Deletion / duplication analysis 5Exonic or whole-gene deletionsUnknown Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. The breakpoints for this deletion can vary slightly; see HGMD.3. Includes the two mutations identified by targeted mutation analysis4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.Testing StrategyTo establish/confirm the diagnosis in a proband Plasma gastrin concentration Molecular genetic testing: Targeted mutation analysis in individuals of Ashkenazi Jewish heritageSequence analysis in individuals not of Ashkenazi Jewish heritageDeletion/duplication analysis if no mutations are detected using the above methods. Note: No information is available regarding the mutation detection frequency of deletion/duplication analysis.Skin biopsy or conjunctival swab if molecular genetic testing is not available and/or informative Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in an affected family member. Note: Carriers are heterozygous for an autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in MCOLN1.
Mucolipidosis IV is a neurodevelopmental disorder that is also neurodegenerative in about 15% of individuals. The phenotype in affected individuals can be considered either typical (~95% of individuals) or atypical (~5% of individuals) [Altarescu et al 2002]. Although individuals with mucolipidosis IV typically survive to adulthood, it is believed that the life expectancy is reduced compared to healthy individuals....
Natural HistoryMucolipidosis IV is a neurodevelopmental disorder that is also neurodegenerative in about 15% of individuals. The phenotype in affected individuals can be considered either typical (~95% of individuals) or atypical (~5% of individuals) [Altarescu et al 2002]. Although individuals with mucolipidosis IV typically survive to adulthood, it is believed that the 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. 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], although some individuals have neurologic deterioration. 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 are common but are infrequently associated with clinical seizures [Siegel et al 1998]. 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 over age five years. Virtually all individuals with mucolipidosis IV develop severe visual impairment by their early teens as a result of the retinal degeneration.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].Iron deficiency occurs in about 50% and iron deficiency anemia, which is usually well tolerated, occurs in about 10% of individuals [Altarescu et al 2002]. The achlorhydria is asymptomatic.The face is not typically coarse.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. 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 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]. The patients 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].
Ashkenazi Jewish individuals usually have the most severe form of the disease. ...
Genotype-Phenotype CorrelationsAshkenazi Jewish individuals usually have the most severe form of the disease. A missense mutation that creates a new preferred splice site of MCOLN1 (c.1406A>G) discovered in a Canadian family from Newfoundland causes an atypical form of mucolipidosis IV, in which affected individuals walk independently and have better communicative skills [Altarescu et al 2002]. Missense mutations were 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 reducing the stability of mucolipin-1. Individuals with these mutations 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 mutation (p.Thr232Pro) in the same region may be explained by the fact that the mutated protein does not reach the endocytic compartment and accumulates in the endoplasmic reticulum [Manzoni et al 2004]. In several individuals from the southeast United States, a p.Asp362Tyr amino acid change was identified in the third transmembrane domain. This mutation was associated with a slower progression of the retinal disease and a relatively mild neurologic phenotype, although membrane preparations containing mucolipin-1 with this mutation had no channel activity [Raychowdhury et al 2004]. Several mutations were discovered in the fourth transmembrane domain, including p.Phe408del, which causes the mildest mucolipidosis IV phenotype known [Altarescu et al 2002]. The protein construct containing this mutation still functions as a channel in liposome preparations and only displays a deficiency in regulation [Raychowdhury et al 2004]. Several other mutations were discovered in the area of 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].
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. ...
Differential DiagnosisBecause 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, mucolipidosis type II, and the mucopolysaccharidoses.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.)Corneal clouding also occurs in the mucopolysaccharidoses (MPSI, MPSIII, MPSIV, MPSVI), in mucolipidosis II and mucolipidosis III (see Mucolipidosis III Alpha/Beta, Mucolipidosis III Gamma), and in GM1 gangliosidosis. 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.
To establish the extent of disease in an individual diagnosed with mucolipidosis IV, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with mucolipidosis IV, the following evaluations are recommended:Ophthalmic examination Brain MRI Iron studies Neurologic evaluation, including EEG Treatment of ManifestationsThe 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 (AEDs) 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 Prevention of Secondary ComplicationsPhysical therapy and rehabilitation can help prevent permanent joint contractures. An oral iron preparation such as a ferrous sulfate is indicated for treatment of iron deficiency anemia resulting from poor absorption of dietary iron.SurveillanceAnnual 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.OtherCorneal transplantation has not been successful because the donor corneal epithelium is eventually replaced by the abnormal host epithelium.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMCOLN119p13.2Mucolipin-1MCOLN1 homepage - Mendelian genesMCOLN1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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) View in own window 252650MUCOLIPIDOSIS IV 605248MUCOLIPIN 1; MCOLN1Molecular 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 mutation 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].Normal allelic variants. MCOLN1 spans 12,300 base pairs and contains 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). Pathologic allelic variants. A variety of mutations cause mucolipidosis IV, including splice mutations, small and large deletions and insertions, and point mutations that either cause stop codons or amino-acid changes in MCOLN1 (Table 3). The two most prevalent mutations cause the majority of mucolipidosis IV in the Ashkenazi Jewish population. One is the splice mutation 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, g.511_6943del, is a deletion mutation that eliminates 6434 bp of DNA, including the first five exons and part of exon 6 of MCOLN1. A Polish individual with a non-Jewish haplotype was found to be heterozygous for this mutation [Sun et al 2000]. Missense mutations 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 mutations not discussed in this review. For more information, see Table A.Table 3. Selected MCOLN1 Pathologic Allelic VariantsView in own windowProtein ChangeDNA ChangeReference Sequence Alias 1c.406-2A>GNM_020533.2 AF287270 IVS3-2A>G g.511_6943del AF287270 6.4-kb deletionp.Thr232Pro c.694A>C NM_020533.2p.Asp362Tyr c.1084G>T p.Phe408del c.1221_1223delCTT p.Phe454_Asn569del c.1406A>G 2g.9107A>G See footnote 3c.1704A>T 3p.Ala539Profs*41 4c.1615delG 4See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. 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. Goldin et al [2008]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 mutations are null alleles resulting in no gene product. When an abnormal gene product exists, it is a nonfunctional protein.