DiagnosisClinical DiagnosisTogether, lissencephaly and subcortical band heterotopia (SBH) comprise the "agyria-pachygyria-band" spectrum of cortical malformations that are caused by deficient neuronal migration during embryogenesis [Barkovich et al 1991, Norman et al 1995]. The term lissencephaly refers to a "smooth brain" with absent gyri (agyria) or abnormally wide gyri (pachygyria). MRI FindingsLissencephalyCerebral gyri are absent or abnormally broad. The cerebral cortex is abnormally thick (12-20 mm; normal: 3-4 mm) [Barkovich et al 1991]. Associated findings in the most common ("classic") form of lissencephaly include:Enlarged lateral ventricles, especially posteriorlyMild hypoplasia of the corpus callosum (the anterior portion often appears flattened)Cavum septi pellucidi et vergae Normal brain stem and cerebellum except for mild vermis hypoplasia in some individualsSubcortical band heterotopia (SBH) A subcortical band of heterotopic gray matter, present just beneath the cortex, is separated from it by a thin zone of normal white matter [Barkovich et al 1994]. The subcortical bands are most often symmetric and diffuse, extending from the frontal to occipital regions; however, they may be asymmetric. Subcortical bands restricted to the frontal lobes are more typically associated with mutations of DCX. (See DCX-Related Disorders.)Subcortical bands restricted to the posterior lobes are more typically associated with LIS1 mutations.The gyral pattern is normal or demonstrates mildly simplified shallow sulci; a normal cortical ribbon is present. Lissencephaly and SBH are graded by anterior-posterior gradient and severity (Table 1 and Figure 1). When the lissencephaly or SBH is more severe posteriorly, it is referred to as a posterior to anterior (p>a) gradient. When more severe anteriorly, it is referred to as an anterior to posterior (a>p) gradient. LIS1 abnormalities generally give rise to a p>a gradient, whereas abnormalities of DCX generally give rise to an a>p gradient [Pilz et al 1998a, Dobyns et al 1999].FigureFigure 1. Brain MRIs of lissencephaly, ranging from grade 1 (the most severe) to grade 6 (subcortical band heterotopia, the least severe). (P) indicates posterior; (A) indicates anterior. Lissencephaly that is more severe posteriorly than anteriorly (best (more...)Table 1. Grading System for Classic Lissencephaly and SBHView in own windowGradientGrade of Severity1a=p ^{1Complete agyria2p>a or 2a>pDiffuse agyria with a few undulations at the frontal or occipital poles3p>a or 3a>pMixed agyria and pachygyria4p>a or 4a>pDiffuse pachygyria, or mixed pachygyria and normal or simplified gyri5a>p (the reverse 5p>a has not been observed)Mixed pachygyria and subcortical band heterotopia6p>a or 6a>pSubcortical band heterotopia only1. With severe grade 1 lissencephaly, it is difficult to determine if a gradient is present. Histologic FindingsClassic lissencephaly. The cortex is abnormally thick and poorly organized with four apparent layers consisting of the following [Crome 1956, Forman et al 2005]:Poorly defined marginal zone with increased cellularitySuperficial cortical gray zone with diffusely scattered neuronsRelatively neuron-sparse zoneDeep cortical gray zone with neurons often oriented in columns. Neurons may be oriented with dendrites extending toward the pial surface or inverted, extending toward the ventricle.SBH. The architecture of the cortex is normal with readily distinguishable white matter including U-fibers, scattered neurons in the outer portion of the bands, a somewhat columnar arrangement of neurons in the inner part of the bands accentuated by radially oriented bundles of myelinated fibers, and scattered inverted neurons [Harding 1996].TestingChromosome analysisHigh-resolution chromosome studies at the 450-band level or higher identify cytogenetically visible deletions or other structural rearrangements of 17p13.3 in approximately 70% of individuals with Miller-Dieker syndrome (MDS), but not isolated lissencephaly sequence (ILS) or SBH [Dobyns et al 1991]. Rarely, individuals with isolated lissencephaly sequence (ILS) have a balanced reciprocal translocation disrupting LIS1.Rarely, individuals with SBH have mosaic deletions of 17p13.3 visible on cytogenetic analysis. Molecular Genetic TestingGene. Abnormalities of LIS1 cause isolated LIS1-associated lissencephaly/SBH [Pilz et al 1998b, Pilz et al 1999, Cardoso et al 2000, Cardoso et al 2002, Sicca et al 2003]. The official gene designation for LIS1 has been changed to PAFAH1B1 (see Tables in Molecular Genetics). However, in this GeneReview LIS1 designation is retained because of its common use in the medical genetics field. Clinical testingFISH testing is performed using a probe containing LIS1 (e.g., PAC95H6). MDS. As currently defined, MDS is associated with deletions that include both LIS1 and YWHAE in 17p13.3 [Pilz et al 1998a, Cardoso et al 2003]. ILS. Approximately 54% of individuals with LIS1-related ILS have a deletion of LIS1 detectable by FISH. Partial LIS1 deletions may not be detectable by FISH. Almost all LIS1 deletions (partial and complete) can be detected by MLPA analysis (see MLPA analysis below).SBH. Mosaic deletions of 17p13.3 involving LIS1 have been observed in two individuals with SBH [unpublished, reviewed by WB Dobyns].Deletion/duplication analysis, testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA, can be accomplished with a variety of methods, such as quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridization (CGH).Array comparative genomic hybridization (aCGH) analysis. Targeted and whole-genome aCGH analyses that contain probes to LIS1 can be used to detect whole-gene deletions of LIS1. However, partial-gene deletions, which appear to be common, may not be detected.MLPA analysis. Intragenic deletions and duplications of LIS1 that range in size from a single exon to multiple exons to the entire gene are present in approximately 14% of individuals with LIS1-related ILS [Haverfield et al 2009, Mei et al 2008] and can be detected by MLPA analysis. This category of deletions/duplications is not detected by FISH or aCGH analysis. Sequence analysis detects: Germline LIS1 mutations in approximately 32% of individuals with LIS1-related ILS. Rarely, mosaic mutations have been identified.On occasion, LIS1 mutations in individuals with LIS1-related SBH. To date, mutations have been identified in four individuals: three who had mosaic mutations and one with an apparent germline mutation [Pilz et al 1999, D’Agostino et al 2002, Sicca et al 2003, Uyanik et al 2007]. Table 2. Molecular Genetic Testing Used in LIS1-Related Lissencephaly/SBHView in own windowGene SymbolTest Method Mutations Detected Frequency of Mutations 1 2Test AvailabilityMDSILSSBHLIS1FISH 3aCGH 4, 5MLPA 5Deletions of LIS1 and adjacent genes/regions100%~54%0.3% 6Clinical MLPA 5Exonic and multiexonic deletions and duplications0~68% (54%+14%)ND 8Sequence analysis Sequence variants 80~32%0.7% 9Data from Pilz et al [1998a], Pilz et al [1998b], Pilz et al [1999], D’Agostino et al [2002], Cardoso et al [2002], Cardoso et al [2003], Sicca et al [2003], Haverfield et al [2009], Mei et al [2008]1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Does not take into account individuals with mutations of DCX, TUBA1A, or other lissencephaly-associated genes, and those in whom no mutations have been identified3. Using the PAC95H6 or Vysis® LIS1 probe4. Array CGH that contains probes that correspond to LIS1; 3/5 cases5. MLPA and aCGH are methods that identify deletions/duplications not detectable by sequence analysis of genomic DNA; other methods including quantitative PCR and real-time PCR may also be used.6. Mosaic deletion or sequence variant; 2/6 cases7. ND = not described8. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. 9. Mosaic deletion or sequence variant; 3/6 cases Issues with interpretation of test results Normal results of FISH analysis using a LIS1-derived probe such as 95H6 do not exclude the presence of the following:A submicroscopic deletion of 17p13. Although the majority of LIS1 may be intact, small regions may be deleted but not detectable (e.g., the promoter, the 5' untranslated region [UTR], or an individual exon).An intragenic mutation of LIS1Normal results of aCGH analysis do not exclude the presence of LIS1 Intragenic deletions or duplications that affect single or multiple exons.For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy The following testing strategies involve testing for deletions and mutations of LIS1 and mutations of DCX, an X-linked gene associated with ILS and SBH, and TUBA1A, an autosomal gene associated with ILS (see Differential Diagnosis). These testing strategies do not take into consideration the gradient or grade of lissencephaly.Testing strategy for probands with isolated lissencephaly Deletion/duplication analysis (e.g., MLPA) detects all large deletions involving LIS1 as well as small exonic deletions and duplications not detected by sequence analysis. Deletions may be detected by FISH or aCGH analysis rather than by MLPA, but the yield is only 54% compared to 68% for MLPA. Thus, MLPA would need to be performed in all individuals in whom FISH analysis or aCGH analysis were negative.Sequence analysis of LIS1 Sequence analysis of DCXMales. When the gradient of lissencephaly seen on brain imaging studies is more severe over the frontal lobes than over the posterior brain regions, DCX sequence analysis may be performed prior to MLPA analysis. Females. The yield is expected to be <5%. DCX mutations were found in two of 50 such females [WB Dobyns, personal observation]. Sequence analysis of TUBA1AChromosome analysis. Only two individuals with balanced reciprocal translocations disrupting LIS1 have been observed (<1%).Testing strategy for probands with SBHSequence analysis of DCX detects mutations in up to 80% of females [Des Portes et al 1998, Gleeson et al 1999, Matsumoto et al 2001] and 30% of males [D’Agostino et al 2002].Deletion/duplication analysis (e.g., MLPA) of DCX detects intragenic deletions in approximately 5%-9% of females [Mei et al 2007, Haverfield et al 2009] Sequence analysis of LIS1 detects mosaic mutations in a few individuals [Pilz et al 1999, D’Agostino et al 2002, Sicca et al 2003]. FISH testing using a LIS1-derived probe detected mosaic deletions of 17p13.3 in two persons with SBH [unpublished, reviewed by WB Dobyns].Sequence analysis of TUBA1A. To date, one person with SBH has been observed with a TUBA1A mutation [unpublished, reviewed by WB Dobyns].Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations of LIS1.}

Natural History The phenotypes associated with mutations of LIS1 comprise a spectrum of severity that can be separated into Miller-Dieker syndrome (MDS), ILS (or isolated lissencephaly) and, on rare occasion, subcortical band heterotopia (SBH).MDS consists of severe lissencephaly (grade 1-2) (see Table 1 and Figure 1), characteristic facial changes, other more variable malformations, and severe neurologic and developmental abnormalities [Dobyns et al 1991, Cardoso et al 2003]. The facial changes consist of high and prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip with downturned vermillion border, and small jaw (Figure 2). Other malformations seen on occasion include omphalocele and congenital heart defects. FigureFigure 2. Two children with Miller-Dieker syndrome showing typical facial features
Photographs have been obtained with consent of the families. ILS consists of more variable lissencephaly (grades 2-4) (see Table 1 and Figure 1), minor facial changes, rare malformations outside of the brain, and similar neurologic and developmental handicaps as in MDS [Dobyns et al 1992]. In both MDS and ILS, the pregnancy may be complicated by polyhydramnios. Affected newborns may appear normal or may have mild to moderate hypotonia, poor feeding, and transient elevations in bilirubin likely related to feeding difficulties [Dobyns et al 1991, Dobyns et al 1992]. At birth, the occipitofrontal circumference (OFC) is typically normal (between the mean and 2 SD below the mean). However, postnatal head growth is slow; most children develop microcephaly by age one year. Prior to the onset of seizures, most infants have mild delay in development and mild hypotonia including poor head control. Some have difficulty with feeding.Children with lissencephaly have epileptic encephalopathies that typically evolve from infantile spasms (West syndrome) to Lennox-Gastaut syndrome of mixed epilepsy with a slow spike and wave pattern on EEG. Overall, seizures occur in more than 90% of children with lissencephaly with onset usually before age six months. Approximately 80% have infantile spasms, although the EEG does not always show the typical hypsarrhythmia pattern. The onset of infantile spasms is typically associated with a precipitous decline in function. After the first months of life, most children have mixed seizure disorders including persisting infantile spasms, focal motor and generalized tonic seizures [Guerrini 2005], complex partial seizures, atypical absences, and atonic and myoclonic seizures. Some children with lissencephaly have characteristic EEG changes, including diffuse high-amplitude fast rhythms that are considered to be highly specific for this malformation [Quirk et al 1993].The developmental prognosis is poor for all children with MDS and for the majority with isolated lissencephaly. Even with good seizure control, the best developmental level achieved by children with MDS or isolated lissencephaly (excluding the few with partial lissencephaly) is the equivalent of about age three to five months. This may include brief visual tracking, rolling over, limited creeping, and very rarely, sitting. With poor seizure control, children with lissencephaly may function at or below the level of a newborn. A few individuals with less severe (grade 4) lissencephaly, especially partial posterior lissencephaly or pachygyria, have a better developmental outcome [Leventer et al 2001].During the first years, neurologic examination typically demonstrates brief visual tracking and response to sounds, axial hypotonia, and mild distal spasticity. Infants often demonstrate abnormal arching (opisthotonus). Later, distal spasticity becomes more prominent although hypotonia remains. Rarely, affected individuals develop moderate spastic quadriplegia and scoliosis. Feeding often improves during the first few months of life, but typically worsens again with seizure onset during the first year of life, and then again at several years of age for various reasons. Children with lissencephaly have poor control of their airways, which predisposes to aspiration pneumonia, the most common terminal event.The prognosis differs somewhat between MDS and isolated lissencephaly. In MDS, death occurs within the first two years in many children, and only a few reach age ten years. The oldest known individual with MDS died at age 17 years. In isolated lissencephaly, approximately 50% live to age ten years, and very few reach age 20 years. The oldest known individual lived to age 30 years. These estimates apply only to individuals with typical lissencephaly affecting the entire brain (the large majority of those with lissencephaly).Only four individuals with SBH associated with LIS1 mutations have been reported, one with a germline mutation and three with mosaic mutations [Pilz et al 1999, D’Agostino et al 2002, Sicca et al 2003, Uyanik et al 2007]. Two other unreported individuals have had mosaic deletions of chromosome 17p13.3 [Author, personal observation].SBH is characterized by normal facial appearance, epilepsy, and intellectual disability. Three of the four individuals with LIS1-related SBH had frequent seizures. One had an IQ of 107 at age seven years that declined to 60 by age 13 years, most likely as a result of severe seizures; one had an IQ of approximately 60; and one had severe intellectual disability. The fourth had attained normal developmental milestones and had language delay at age three years [Uyanik et al 2007]. In general individuals with SBH live into adult life. No reliable data regarding life span exist; it is likely to be shortened in those with severe intellectual disability, intractable epilepsy, or both.

Differential DiagnosisThe greatest difficulty in diagnosis of lissencephaly and subcortical band heterotopia (SBH) is recognizing the malformation. Several types of lissencephaly have been described, although they have overlapping features (Table 3). The most common are classic lissencephaly (including SBH) and cobblestone complex. Table 3. Types of LissencephalyView in own windowTypeDescriptionGenesInheritance PatternClassic lissencephalyVery thick cortex (15-20 mm), normal corpus callosum, and cerebellar vermis (or mild hypoplasia)LIS1ADDCXX-linkedTUBA1AADCobblestone cortical malformation (lissencephaly)Pebbled brain surface, moderately thick 5-10 mm cortex (unless thinned by hydrocephalus), diffuse or patchy white matter abnormality, brain stem and cerebellar hypoplasiaFKTNARFKRPLARGEPOMGnT1POMTPOMT2GPR56Lissencephaly with agenesis of the corpus callosumLissencephaly with total or severe partial agenesis of the corpus callosumARXX-linkedLissencephaly with cerebellar hypoplasiaLissencephaly with moderate to severe cerebellar hypoplasiaRELNARVLDLRMicrolissencephalyBirth OFC -3 SD or small, thick cortexNANAAD = Autosomal dominantAR = Autosomal recessiveNA = Not applicableOFC = Occipital frontal circumferenceAbout half of individuals reported to have lissencephaly on a brain imaging study actually have another malformation, most often severe congenital microcephaly or polymicrogyria, frequently described as "pachygyria" [personal observation]. (See Polymicrogyria Overview.)Clinical features can also help distinguish children who have lissencephaly from those who have other brain malformations. Children with lissencephaly usually have normal or slightly small OFC at birth (> -3 SD) and diffuse hypotonia except for mildly increased tone at the wrists and ankles. Children with severe congenital (i.e., primary) microcephaly and gyral abnormalities have smaller birth OFC (≤ -3 SD) and may be hypotonic or spastic. Infants with polymicrogyria, especially when the frontal lobes are involved, frequently have spastic quadriparesis. The differential diagnosis of classic lissencephaly includes the LIS1-related malformations, DCX-related malformations, TUBA1A-related malformations and the rare Baraitser-Winter syndrome (BWS) [Dobyns et al 1991, Dobyns et al 1992, Pilz et al 1998a, Pilz et al 1998b, Dobyns et al 1999, Matsumoto et al 2001, Ross et al 2001, Rossi et al 2003, Poirier et al 2007]. These disorders are distinguished by the mode of inheritance, grade and gradient of lissencephaly or SBH (Table 1), presence of other congenital anomalies, and results of molecular genetic testing. Classic lissencephaly associated with deletions or intragenic mutations of LIS1 is more common than classic lissencephaly associated with mutations of DCX, located on the X chromosome [Pilz et al 1998b], and classic lissencephaly associated with mutations in TUBA1A. SBH in females associated with mutations of DCX is far more common than SBH in females with LIS1 mutations [Pilz et al 1999, D’Agostino et al 2002, Sicca et al 2003]. LIS1-related malformations are characterized by a p>a gradient (see Table 1). DCX-related malformations are associated with an a>p gradient [Pilz et al 1998b, Dobyns et al 1999]. However, in severe classic lissencephaly or SBH the gradient may be difficult to discern.TUBA1A-related malformations, like LIS-1 related malformations, are characterized by a p>a gradient similar. The lissencephaly phenotype associated with mutations in these two genes may be indistinguishable. The TUBA1A-related malformation generally appears to be more severe than the LIS1-related malformation [Poirier et al 2007].Baraitser-Winter syndrome is characterized by: lissencephaly with an a>p gradient similar to that of DCX-related malformations; trigonocephaly; shallow orbits; ptosis; and colobomas of the iris, choroid, or both [Ramer et al 1995, Rossi et al 2003]. Lissencephaly with agenesis of the corpus callosum is typically associated with mutations in ARX. The XLAG (X-linked lissencephaly with abnormal genitalia) phenotype in severely affected individuals with a 46,XY karyotype differs significantly from the phenotype associated with mutations of either LIS1 or DCX. XLAG is characterized by congenital or postnatal microcephaly, neonatal-onset intractable epilepsy, poor temperature regulation, chronic diarrhea, and abnormal genitalia [Kato & Dobyns 2003, Kato et al 2004]. The cobblestone cortical malformation (lissencephaly) syndromes (Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy) have many clinical differences including frequent hydrocephalus and cerebellar hypoplasia, many different eye anomalies, and congenital muscular dystrophy (see Congenital Muscular Dystrophy Overview), and manifest by hypotonia and elevated serum creatine kinase concentrations.

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with LIS1-associated lissencephaly/ subcortical band heterotopia (SBH), the following evaluations are recommended:GrowthFeeding and nutritionRespiratory statusDevelopmentSeizures. Whenever any unusual spells or any developmental regression is noted, an EEG should be performed.MRI should be interpreted carefully to provide as much prognostic information as possible. Note: Although most affected individuals have severe to profound intellectual disability, a minority have less extensive lissencephaly that results in only moderate intellectual disability, and a few have limited malformations that allow near-normal development. In the latter, the lissencephaly or SBH is typically less severe and less extensive on MRI. The resolution of brain CT scan is not usually sufficient to allow this. Treatment of Manifestations Parents seem best able to deal with this severe disorder when accurate information regarding the prognosis is given as soon as possible after the diagnosis is recognized. For those with severe lissencephaly, it is usually appropriate to discuss limitations of care, such as "do not resuscitate" (DNR) orders, in the event of severe illnesses.Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life. But they often worsen again with intercurrent illnesses and with advancing age and size. At least half of children with LIS1-related lissencephaly (but not SBH) eventually have a gastrostomy tube placed for feeding.Management of seizures in children with ILS or SBH is based on the specific seizure type and frequency. In general, seizures should be treated promptly and aggressively by specialists, as poor seizure control frequently results in decline in function and health. The response to treatment is typically similar to that in children with seizures due to other causes. 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.

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. LIS1-Associated Lissencephaly/Subcortical Band Heterotopia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPAFAH1B117p13​.3Platelet-activating factor acetylhydrolase IB subunit alphaPAFAH1B1 homepage - Mendelian genesPAFAH1B1Data 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 LIS1-Associated Lissencephaly/Subcortical Band Heterotopia (View All in OMIM) View in own window 247200MILLER-DIEKER LISSENCEPHALY SYNDROME; MDLS 601545PLATELET-ACTIVATING FACTOR ACETYLHYDROLASE, ISOFORM 1B, ALPHA SUBUNIT; PAFAH1B1 607432LISSENCEPHALY 1; LIS1Normal allelic variants. LIS1 (officially designated as PAFAH1B1, but referred to here as LIS1 because of its common use in the medical genetics field) is approximately 92 kb in size and consists of 11 exons. The coding region is 1230 bp, with the AUG start codon located in exon 2, and it encodes a protein of 410 amino acids called PAFAH1B1 (platelet-activating factor acetylhydrolase IB alpha subunit, also known as brain isoform 1b) [Reiner et al 1993]. There are two alternative transcripts (5.5 kb and 7.5 kb) that differ in the length at their respective 3’ UTR regions; both transcripts are expressed ubiquitously [Hattori et al 1994, Lo Nigro et al 1997]. To date, approximately 12 different polymorphisms have been identified in LIS1 (not all have been published). The polymorphic changes that have been identified are thought not to be disease causing, as they have either been found in individuals in whom a clearly deleterious mutation is also present or in individuals without the disease. Most of the polymorphic changes represent rare variants, with the exception of two polymorphisms in the 3’ UTR (c.X3T>G and c.X17C>T; see Table 4) that occur at frequencies of approximately 10% and 40% respectively [Koch et al 1996, Cardoso et al 2000].Pathologic allelic variants. More than 78 different disease-causing LIS1 (PAFAH1B1) mutations have been described [Cardoso et al 2002; Uyanik et al 2007; Author, unpublished]. Most are private mutations; however, a few recurrent mutations have been described, including c.162delA and c.162dupA, which occur in a small stretch of adenine residues, and c.1050delG and c.1050dupG, which occur in a small stretch of guanine residues. Mutations appear to be evenly distributed throughout the gene. No predominant common mutation has been identified in any population.Intragenic deletions and duplications of LIS1 that range from single-exon deletions or duplications to deletions of the entire coding region have been described; to date, 27 partial deletions and seven partial duplications of LIS1 have been identified [Mei et al 2008, Haverfield et al 2009]. These partial deletions and duplications appear to be spread throughout the gene. Microdeletions of the 17p13.3 region that delete all of LIS1 have been described in approximately 40% of individuals with ILS and differ with regard to size and break points. 17p13.3 microdeletions have been identified in affected individuals of different ethnic groups.Table 4. Selected PAFAH1B1 (LIS1) Recurrent Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequences Normalc.X3T>C
(1233*3T>G)--NM_000430​.3
NP_000421​.1c.X17C>T
(1233*17C>T)--Pathologicc.162delAp.Lys54Asnfs*15c.162dupA
(c.162_163insA)p.Trp55Metfs*6c.1050delGp.Lys351Serfs*4c.1050dupG
(c.1050_1051insG)p.Lys351Glufs*8c.569-10T>C
(IVS6-10T>C)--c.1002+1G>A
(IVS9+1G>A)--See 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 conventions Normal gene product. The PAFAH1B1 protein is a 45-kd protein that contains 410 amino acids and is highly conserved among species. The main functional domains of this protein are a LisH motif at the N terminus, followed by a coiled-coil region and seven WD40 repeats at the C terminus [Reiner et al 1993, Cardoso et al 2000]. The LisH domain, coiled-coil domain, and WD40 repeats are important for dimerization and are involved in protein/protein interactions and are essential for PAFAH1B1 function [Sapir et al 1999, Efimov & Morris 2000, Sweeney et al 2000, Ahn & Morris 2001, Cahana et al 2001, Kim et al 2004].The PAFAH1B1 protein has two main functions: (1) it forms a trimeric complex with the PAFAH1B2 and PAFAH1B3 proteins to regulate the level of platelet activating factor in the brain and this is thought to be critical for correct neuronal migration [Albrecht et al 1996, Bix & Clark 1998]; (2) it has been shown to play a central role in the organization of the cytoskeleton by the interaction with proteins including tubulin (the major component of microtubules) as well as proteins associated with the centrosome and involved in microtubule dynamics (e.g., cyoplasmic dynein, dynactin, NUDE, and NUDEL), in turn affecting neuronal proliferation and migration [Faulkner et al 2000, Feng et al 2000, Niethammer et al 2000, Smith et al 2000, Suzuki et al 2007]. The PAFAH1B1 protein is also thought to be an integral component of the Reelin signaling pathway [Assadi et al 2003] Abnormal gene product. Mutations in LIS1 result in a reduction in the amount of correctly folded PAFAH1B1 protein [Sapir et al 1999]. Modeling studies of LIS1 mutations have shown that they abolish the binding of its protein, PAFAH1B1, with protein partners such as PAFAH1B2, PAFAH1B3, NUDE, or NUDEL [Sapir et al 1999, Feng et al 2000, Sasaki et al 2000, Sweeney et al 2000]. This in turn interferes with functions such as neuroblast proliferation and migration. LIS1 RNA interference studies indicate that an abnormal LIS1 gene product disrupts the production of neurons in the developing brain as well as their migration [Tsai et al 2005]. Both non-radial cell migration (inhibitory interneurons) and radial migration (excitatory projection neurons) appear to be affected [Fleck et al 2000, Pancoast et al 2005].