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Hereditary Sensory and Autonomic Neuropathy Type II

Synonyms: Hereditary Sensory and Autonomic Neuropathy Type 2, HSANII, HSAN2
, MD
Institute of Human Genetics
University Hospital Jena
Jena, Germany

Initial Posting: ; Last Revision: November 3, 2011.

Summary

Disease characteristics. Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.

Diagnosis/testing. Diagnosis is based on clinical findings and molecular genetic testing of WNK1 (previously HSN2) (type HSAN2A), FAM134B (type HSAN2B) and KIF1A (type HSAN2C), the only genes in which mutation is known to cause HSAN2.

Management. Treatment of manifestations: Treatment is symptomatic and often involves a team including neurologists, orthopedic surgeons, and physiotherapists. Training in the care of the sensory-impaired limb, often in a diabetic clinic, is important and includes self-examination especially of the feet for any signs of trauma. To prevent osteomyelitis, and hence amputations, wounds require cleaning and protection along with antiseptic treatment. To prevent callous formation the skin of neuropathic limbs requires hydration and lipid-based unguents. Appropriate shoes and socks are recommended.

Surveillance: The feet should be inspected daily for injuries or sources of wear. Annual follow up in centers with comprehensive care of diabetics and/or persons with Charcot-Marie-Tooth neuropathy is recommended.

Genetic counseling. HSAN2, which includes HSAN2A, HSAN2B, and HSAN2C, 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 of at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

The clinical diagnosis of hereditary sensory and autonomic neuropathy type II (HSAN2) is based on the presence of the following:

  • Congenital or early onset (first to second decade) sensory deficit
  • Sensory loss affecting all modalities
  • Ulcerations of hands/feet often requiring amputations
  • Acral mutilations
  • Painless fractures and neuropathic arthropathy in some
  • Varying degree of autonomic involvement: hyperhidrosis, urinary incontinence, and slow pupillary reaction to light.
    Note: Autonomic disturbances seem to be less prominent in HSAN2 compared to the other autosomal recessive sensory neuropathies (HSAN3, HSAN4, HSAN5).
  • Family history consistent with autosomal recessive inheritance

Testing

Electrophysiology reveals the following:

  • Reduced/absent sensory nerve action potentials
  • Preserved or reduced motor nerve conduction velocities (NCV)
  • Variably reduced compound muscle action potentials (CMAP)

Histopathology: Sural nerve biopsy shows signs of an axonal sensory neuropathy, pronounced absence of (small) myelinated fibers, and decreased unmyelinated fibers.

Molecular Genetic Testing

Genes. The three types of hereditary sensory and autonomic neuropathy type II (HSAN2) and associated genes:

  • HSAN2A. WNK1 (previously named HSN2, a gene symbol that is now retired). The previously designated HSN2 was first reported as a single-exon gene located in intron 8 of WNK1, with both genes transcribed from the same strand [Lafreniere et al 2004]. Subsequently, HSN2 was found to be an alternatively spliced exon present in a nervous system-specific isoform of WNK1 [Shekarabi et al 2008]. This exon, the so-called ‘HSN2’ exon, is exon 10 in the reference sequence of the nervous system-specific WNK1 isoform variant 4 (see Molecular Genetics for details).
  • HSAN2B. FAM134B (previously known as JK-1)
  • HSAN2C. KIF1A

Clinical testing

  • WNK1
    Sequence analysis focuses on analysis of the ‘HSN2 exon’ of the genomic sequence of WNK1. Because mutations in other exons of WNK1 may also contribute to the HSAN2A phenotype, sequence analysis of all known exons from genomic DNA may be necessary if only one mutation is found in the ‘HSN2’ exon.
    Note: Homozygous or compound heterozygous null alleles affecting all WNK1 isoforms are speculated to be embryonically lethal.
  • FAM134B
    Sequence analysis. Thus far, diagnosis of HSAN2B has been confirmed in five families by FAM134B sequence analysis.

Research testing

  • KIF1A
    Sequence analysis. The mutations reported are particularly located in an alternatively spliced exon. This should be taken into account when performing molecular genetic testing.

Table 1. Summary of Molecular Genetic Testing Used in Hereditary Sensory and Autonomic Neuropathy Type II

HSAN2 TypeGene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
HSAN2AWNK1Sequence analysis 4Sequence variants 5Unknown
HSAN2BFAM134B
HSAN2CKIF1A

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. To date, all WNK1, FAM134B, and KIF1A mutations that cause HSAN2 are nonsense, frameshift, or splice-site mutations. Copy number variants in the genes have not been addressed in the current literature.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of HSAN2 is established in individuals who meet clinical diagnostic criteria and who have a disease-causing mutation in both alleles of either WNK1, FAM134B, or KIF1A.

In families with parental consanguinity, segregation analysis for WNK1, FAM134B, and KIF1A polymorphic markers may identify which gene is most likely to be causal and therefore should be sequenced first.

Affected individuals with WNK1 and KIF1A mutations did not show clinical autonomic dysfunction in contrast to individuals with FAM134B mutations. However, due to the small number of patients reported with HSAN2 this may not be a sufficient criterion to distinguish between these HSAN2 subtypes. Distal motor involvement has been described in KIF1A-related disease.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder, but persons who are heterozygous for WNK1 mutations that cause HSAN2A are reported to be more sensitive to thermal stimuli [Loggia et al 2009].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

The hereditary sensory and autonomic neuropathies present a genetically and clinically heterogeneous group of neurodegenerative disorders of the peripheral nervous system. The published clinical descriptions of hereditary sensory and autonomic neuropathy type II (HSAN2) are inconsistent, possibly in part as a result of reports that lack molecular genetic confirmation of the diagnosis. Clinically, WNK1-related HSAN (HSAN2A), FAM134B-related HSAN (HSAN2B) and KIF1A-related HSAN (HSAN2C) appear to be very similar but may actually be distinguishable as additional cases are described in the future. Autonomic dysfunction might be more pronounced in FAM134B-related neuropathy and individuals with KIF1A-related HSAN also showed distal muscle weakness.

Typically in mutation-proven HSAN2, the onset is in the first two decades (often before puberty). It is characterized by progressive numbness of the hands and feet, together with reduced sensation to pain, temperature, and touch. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced.

Neuropathic skin tends to produce excessive keratin and hyperkeratosis that may be forced down into the deeper layers of soft tissue and/or may crack, promoting ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Secondary muscle atrophy and Charcot joints may occur. Painless fractures can complicate the disease.

Mental development is usually normal.

Autonomic disturbances seem to be less pronounced than in the other autosomal recessive sensory neuropathies. Sweating and tearing are usually normal but hyperhidrosis is present in some cases. Tonic pupils are observed. With progression of the disease urinary incontinence is reported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known. Inter- and intrafamilial phenotypic variability is reported.

Nomenclature

HSAN2 has also been reported as the following:

  • Morvan´s disease
  • Congenital sensory neuropathy
  • Neurogenic acroosteolysis
  • Hereditary sensory radicular neuropathy

Dyck proposed five different HSAN types on the basis of clinical symptoms and nerve biopsy specimens [Dyck 1993]. This classification still stands after the molecular characterization of the subtypes, but additional genetic and phenotypic heterogeneity has been included [Verhoeven et al 2006], suggesting a need for a detailed classification based on the underlying gene defects.

Prevalence

The worldwide prevalence of HSAN2 is unknown. For comparison, the overall prevalence of the closely related hereditary motor and sensory neuropathies (HMSN or Charcot-Marie-Tooth disease) is on the order of 30:100,000, and hereditary sensory and autonomic neuropathies (HSAN) occur with markedly lower frequency.

Clustering of cases of HSAN2A in eastern Canada is the result of relatively common founder mutations [Roddier et al 2005].

Differential Diagnosis

Disorders accompanied by self-mutilating behavior resemble some aspects of the congenital forms of HSAN including Lesch-Nyhan syndrome or untreated phenylketonuria. Diabetic neuropathy shares some aspects of adult-onset HSAN. Confusion of HSAN with leprosy is reported in some cases.

Clinical overlap is also observed between adult-onset HSAN and Charcot-Marie-Tooth Neuropathy (CMT). For example, CMT2J (OMIM 607736), caused by the p.Thr124Met mutation in MPZ, encoding myelin protein zero, is characterized by severe sensory loss, but no ulcerations [De Jonghe et al 1999].

CMT2B, caused by mutations in RAB7A, is characterized by distal muscle weakness and wasting as often the first and most prominent sign of the disease [Verhoeven et al 2003]. The disease is accompanied by sensory loss of all modalities with a high frequency of foot ulcers necessitating amputations. Nerve conduction velocity studies indicate a primarily axonal neuropathy. (See Charcot-Marie-Tooth Neuropathy Type 2)

Hereditary sensory and autonomic neuropathy type I (HSAN1) is an autosomal-dominant genetically heterogeneous disorder:

  • HSAN1A and HSAN1C (OMIM 162400, OMIM 613640) are caused by mutations in SPTLC1 (HSAN1A) [Bejaoui et al 2001, Dawkins et al 2001] and SPTLC2 (HSAN1C) [Rotthier et al 2010]. The SPT enzymes, encoded by these genes catalyze the de novo synthesis of sphingolipids. Sensory loss in these conditions usually starts in the adult. In rare cases early onset of symptoms is also reported. Dysesthesia with characteristic lancinating pain helps in clinical diagnosis but can be absent. Painless injuries and osteomyelitis requiring amputations are reported as well. The disease can be associated with sensorineural deafness. Motor involvement is mild to severe (including wheelchair requirement). Visceral autonomic features seem to be absent.
  • HSAN1B (OMIM 608088) with autosomal dominant inheritance is an adult-onset sensory neuropathy with cough and gastroesophageal reflux. This entity has been mapped to 3p24-p22 and was described in two independent families, but to date no causative mutation has been identified.
  • HSN1D (OMIM 613708). Mutations in ATL1, known to be associated with hereditary spastic paraplegia 3A (SPG3A), have also been identified in individuals with HSAN [Guelly et al 2011].
  • HSN1E (OMIM 614116). Hereditary sensory neuropathy with dementia and hearing loss is an adult-onset autosomal dominant condition caused by missense mutations in DNMT1, encoding DNA methyltransferase 1 [Klein et al 2011]. Affected persons typically have early mortality and often require total care because of dementia, hearing loss, and loss of ambulation from predominant sensory ataxia.

Hereditary sensory and autonomic neuropathy type III (HSAN3, Riley-Day syndrome, or familial dysautonomia) is a sensory neuropathy characterized by prominent autonomic manifestation. Absence of tears (alacrima) with emotional crying is one of the cardinal features. Lingual fungiform papillae are also absent. Hypotonia and feeding difficulties contribute to delay in acquisition of motor milestones. Affected individuals have gastrointestinal dysfunction, nausea and vomiting crises, recurrent pneumonia, and cardiovascular instability culminating in autonomic crisis. Sensitivity to pain and temperature perception is reduced but usually not as profoundly as with the other HSAN disorders. Prevalence of HSAN3 is high in individuals of Ashkenazi Jewish descent as a result of two founder mutations that account for more than 99% of mutant alleles. HSAN3 is caused by mutation in IKBKAP [Anderson et al 2001, Slaugenhaupt et al 2001].

Hereditary sensory and autonomic neuropathy type IV (HSAN4, also termed “Congenital insensitivity to pain with anhidrosis” [CIPA]) is characterized by profound sensory loss predominantly affecting perception of pain and temperature. As a consequence of the early onset of reduced pain perception, self-mutilating behavior (biting of tongue, lips, and fingertips) is common. Repeated fractures are secondary consequences. Anhidrosis caused by lack of sweat gland innervation results in poor thermoregulation and can cause recurrent febrile episodes which can be fatal. Intellectual disability is variable. Mutations in NTRK1 are causative [Indo et al 1996].

Hereditary sensory and autonomic neuropathy type V (HSAN5) shows marked clinical overlap to HSAN4 and has been reported to be caused by mutations in NGFB [Einarsdottir et al 2004, Carvalho et al 2011]. However, some cases of clinically diagnosed HSAN5 seem to be caused by NTRK1 mutations as well. In HSAN5 anhidrosis is less prominent than in HSAN4. Selective loss of deep pain perception, painless fractures, and joint deformities have been described for this entity.

Congenital indifference to pain (CIP) belongs to the group of SCN9A-related disorders and is caused by loss-of-function mutations in SCN9A, encoding the Nav1.7 channel non-redundantly required for nociception (OMIM 243000) [Cox et al 2006]. CIP is an inherited autosomal recessive channelopathy. Individuals with CIP have painless injuries beginning in infancy but otherwise normal sensory responses. The complications of the disease follow the inability to feel pain, and most individuals have injuries to the lips or tongue caused by biting themselves in early childhood. Patients usually have a history of unnoticed fractures. The insensitivity to pain seems to result from a defect in nociceptive transmission and not from axonal degeneration, as the nerves appear to be largely normal on examination.

Table 2. Comparison of HSAN subtypes

SubtypeTypical Onset AgeMOIOMIMGenesClinical SignsSural Nerve Biopsy 1
HSAN1AdultAD162400
613640
613708
SPTLC1
SPTLC2
ATL1
  • Loss of pain and temperature sensation
  • Osteomyelitis
  • Lancinating pain
  • Distal motor involvement (variable)
  • Facultative deafness
  • No visceral signs of autonomic involvement
Distal loss of unmyelinated and myelinated fibers
CMT2BAdultAD600882RAB7A
  • Acral ulcero-mutilating sensory neuropathy
  • Motor features are common
Reduced density of myelinated fibers; larger ones more affected
HSAN2ChildhoodAR201300
613115
614213
WNK1
FAM134B
KIF1A
  • Mutilations (hands, feet)
  • Acroosteolysis
  • Sensory loss
  • Absent or weak tendon reflexes
  • No myelinated fibers
  • Fewer unmyelinated fibers
HSAN3CongenitalAR223900IKBKAP
  • Prominent autonomic disturbances (vomiting/poor feeding, defective lacrimation, pyrexia, cardiovascular instability)
  • Hypotonia
  • Decreased or absent deep tendon reflexes
  • No fungiform papillae of the tongue
  • Hyperhidrosis, predominantly Ashkenazi Jews affected
  • Normal number of myelinated fibers
    Severe decrease of unmyelinated fibers
HSAN4CongenitalAR256800NTRK1
  • No response to painful stimuli
  • Fever episodes
  • Sweat glands present but no sweating
  • ID in some cases
  • Corneal lesions
  • Joint deformities
  • Normal muscle strength/tendon reflexes
  • No unmyelinated axons
  • Fewer small myelinated neurons
  • Normal density of myelinated fibers
HSAN5CongenitalAR608654NGFB
NTRK1
  • No response to painful stimuli
  • No ID
  • Joint deformities
  • Fractures
  • Normal muscle strength/tendon reflexes
Selective decrease of small myelinated & unmyelinated fibers

MOI = mode of inheritance

ID = intellectual disability

1. According to Schenone [2005]

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with hereditary sensory and autonomic neuropathy type II (HSAN2) the following evaluations are recommended:

  • Neurologic examination to determine extent of sensory loss and involvement of autonomic and motor nervous system
  • Nerve conduction velocity (NCV)

Treatment of Manifestations

Treatment is symptomatic and often involves a team including neurologists, orthopedic surgeons, and physiotherapists.

Training in the care of the sensory-impaired limb is important and includes self-examination especially of the feet for any signs of trauma. A diabetic clinic is a good source of advice. Appropriate shoes and socks are recommended.

It is best to prevent callous formation in neuropathic skin; once present, calluses should be treated with hydration and lipid-based unguents to prevent cracking and may require medical consultation.

Cleaning and protection of wounds on neuropathic limbs in combination with antiseptic treatment to eradicate infections help prevent osteomyelitis and amputations.

Surveillance

The feet in particular should be inspected daily for injuries and sources of wear.

Patients should be followed annually by centers with comprehensive care for diabetes and/or CMT.

Agents/Circumstances to Avoid

Avoid ill-fitting shoes or other sources of trauma to the feet or hands (e.g., use protective gloves when handling hot items when cooking).

Evaluation of Relatives at Risk

Clinical evaluation and/or molecular genetic testing of at-risk sibs in early childhood are recommended in order to identify those who will develop sensory loss so that protective measures can be instituted early in order to prevent injury to limbs and/or self-mutilation.

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

Hereditary sensory and autonomic neuropathy type II (HSAN2), which includes HSAN2A, HSAN2B, and HSAN2C, 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 mutant allele).
  • Heterozygotes (carriers) are asymptomatic except for the report of increased sensitivity to thermal stimuli of heterozygote carriers of WNK1 mutations that cause HSAN2A.

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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic (see exception in Parents of a proband).

Offspring of a proband. Unless an individual with HSAN2 has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers).

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing of relatives at risk for a WNK1, FAM134B, or KIF1A mutation is possible if the disease-causing mutations in the family have been identified.

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 affected, 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 disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk may be available through laboratories that offer either testing for the gene of interest or custom testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations 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.

No specific resources for Hereditary Sensory and Autonomic Neuropathy Type II have been identified by GeneReviews staff.

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. Hereditary Sensory and Autonomic Neuropathy Type II: Genes and Databases

Data 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 Hereditary Sensory and Autonomic Neuropathy Type II (View All in OMIM)

201300NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IIA; HSAN2A
601255KINESIN FAMILY MEMBER 1A; KIF1A
605232PROTEIN KINASE, LYSINE-DEFICIENT 1; WNK1
613114FAMILY WITH SEQUENCE SIMILARITY 134, MEMBER B; FAM134B
613115NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IIB; HSAN2B
614213NEUROPATHY, HEREDITARY SENSORY, TYPE IIC; HSN2C

Molecular Genetic Pathogenesis

Motor and sensory neuronal processes in humans extend for one meter or more. The extraordinary length and polarity of these cells thus require specialized anterograde transport processes to supply the distal ends of the projections with nutrients, cytoskeletal components, organelles, synaptic vesicle precursors and lipids, since synthesis of these components largely occurs in the cell soma. Conversely, material intended for degradation has to be transported in a retrograde manner to the cell soma. The same logistic challenge applies to intracellular signals, both anterogradely and retrogradely.

Thus, neurons with long projections seem to be particularly susceptible to impairment in cellular processes such as trafficking, transport, energy utilization, signaling, and cytoskeletal organization in a length-dependent manner, meaning that degeneration and clinical perturbations are maximal at the distal ends of the neuronal projections.

The serine/threonine-protein kinase WNK1 is a known player in the regulation of the blood pressure via reabsorption of ions in the kidney. In addition, an alternatively-spliced nervous system-specific WNK1 isoform is present in the cell body of sensory ganglia neurons and particularly in neuronal projections. Mutations in this nervous system-specific isoform, which includes the ‘HSN2exon, cause HSAN2A disease. Whether the WNK1 protein from this isoform is involved in ion fluxes in the periphery of neurons is speculative. In vitro cellular assays showed WNK1 protein as a signaling molecule involved in the regulation of neurite extensions via LINGO-1, a mediator of the intracellular signaling in response to myelin-associated inhibitors [Zhang et al 2009].

The presence of the WNK1 protein isoform with the ‘HSN2exon in satellite and Schwann cells could argue for an influence of these cell types in modulating the disease. The expression of this isoform in fibers of the Lissauer tract [Shekarabi et al 2008] may also be relevant for the development of clinical symptoms, as these neurons have been reported to be missing in congenital insensitivity to pain with anhidrosis.

KIF1A is a molecular motor protein of the kinesin family. It is involved in axonal transport of synaptic vesicles and was identified as an interaction partner of the neuron-specific isoform of WNK1. Thus, KIF1A could be responsible for the anterograde transport of WNK1 along axons and explain the HSAN phenotype associated with mutations in the gene, but should be important for the transport of different classes of molecules along the long nerve processes. Interestingly, mutations in a close homolog, KIF1B, result in autosomal dominant axonal Charcot-Marie-Tooth disease [Zhao et al 2001] (HMSN2A1; OMIM 118210).

The protein encoded by FAM134B was detected in the Golgi apparatus of sensory ganglia neurons and could be localized in the endoplasmic reticulum as well [Kurth et al 2009]. The protein contributes to the structure of the cis-Golgi compartment and alterations in the Golgi architecture as a result of its dysfunction could impair various cellular functions related to axonal survival. Proper function of the Golgi apparatus as one of the central stations in sorting modification of proteins and lipids is indispensable for axonal maintenance.

WNK1

Gene structure. The WNK1 transcript that includes the ‘HSN2exon encodes transcript variant 4 of WNK1 and comprises 28 exons (NM_001184985.1). See Entrez Gene for a detailed description of the WNK1 isoforms. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The HSAN2-causing mutations in WNK1 reported to date are frameshift or nonsense mutations in exon 10. Compound heterozygosity for a truncating mutation in exon 6 of WNK1 (NM_001184985.1) and a mutation in the so-called ‘HSN2’ exon (exon 10 in NM_001184985.1) is reported in one individual with HSAN2A [Shekarabi et al 2008]. Founder mutations have been reported in French Canadians [Roddier et al 2005]; three are listed in Table 3. Mutations have been confirmed in different populations [Rivière et al 2004, Cho et al 2006, Coen et al 2006, Takagi et al 2006].

Table 3. Selected WKN1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.2697delA 2
(594delA) 3
p.Glu899AspfsTer10 2
(Glu198AspfsTer10) 3
NM_001184985​.1
NP_001171914​.1
c.3021dupA 2
(918_919insA) 3
p.Ser1008IlefsTer13 2
(Ser307IlefsTer13) 3
c.3046C>T 2
(943C>T) 3
p.Gln1016Ter 2
(Gln315Ter) 3

Note on variant classification: Variants listed in the table have been provided by the author. 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; see footnote 3.

2. Nucleotide and amino acid nomenclature is based on the reference sequences for WNK1 transcript variant 4 NM_001184985​.1. In this transcript, the ‘HSN2exon is number 10. All of the mutations in this table are in exon 10.

3. The alias names for nucleotide and amino acid changes are derived from Lafreniere et al [2004] based on the original identification and numbering of the purported gene HSN2 (UCSC HSN2 uc001qiq​.2 protein sequence). The first codon of the HSN2 exon of WNK1 is located 12 amino acids 3´ of the initially supposed Met start-codon of the single-exon HSN2 transcript; mutations in parentheses in Table 3 and in Lafreniere et al [2004] are numbered accordingly.

Normal gene product. NP_001171914.1 serine/threonine-protein kinase WNK1 isoform 4 has 2642 amino acid residues. It encodes a member of the WNK subfamily of serine/threonine protein kinases. Several alternatively spliced transcript variants have been described. WNK1 is a key regulator of blood pressure by controlling the transport of sodium and chloride ions [Kahle et al 2008]. The kidney-specific WNK1 protein is also an important physiologic regulator of renal K(+) excretion by participating in the regulation of a number of K+ channels including ROMK1, Na+/K+/2Cl, and Na+/Cl cotransporters including NKCCs and NCCs. The function of the nervous system-specific isoform of WNK1 is less clear.

Abnormal gene product. The HSAN2A-causing mutations reported to date in WNK1 transcript variant NM_001184985.1, which includes exon 10 (the so-called ‘HSN2’ exon), should invariably lead to severe protein truncation and/or nonsense-mediated mRNA decay compatible with loss of function.

FAM134B

Gene structure. FAM134B comprises nine exons (isoform 1, NM_001034850.1). Nonsynonymous coding normal variants are found, for example, in exon 9 (Table 4). FAM134B isoform 2 (NM_019000.3) differs in the 5' UTR and coding sequence compared to variant 1 and seems to be the major variant in testis. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. FAM134B mutations are found over the entire coding sequence and are loss-of-function mutations. Of the five homozygous mutations reported to date, three are nonsense mutations, one is a frameshift mutation, and one is a splice-site mutation [Kurth et al 2009, Murphy et al 2012].

Table 4. Selected FAM134B Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Benignc.1135C>G
rs34432513 1
p.Gln379Glu NM_001034850​.1
NP_001030022​.1
c.1145G>C
rs61733811 1
p.Ser382Thr
Pathogenicc.18_19delTCp.Pro7GlyfsTer133
c.433C>Tp.Gln145Ter
c.873+2T>C--
c.926C>Gp.Ser309Ter

Note on variant classification: Variants listed in the table have been provided by the author. 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. rs#: Reference SNP number (www​.ncbi.nlm.nih.gov/snp)

Normal gene product. FAM134B encodes a protein with putative transmembrane spans. The protein resides in components of the early secretory pathway and is enriched in the cis-Golgi compartment of sensory ganglia neurons. FAM134B contributes to the architecture of the Golgi apparatus.

Abnormal gene product. The mutations in FAM134B reported so far lead to severe protein truncation and/or nonsense-mediated mRNA decay compatible with loss of function [Kurth et al 2009].

KIF1A

Gene structure. KIF1A comprises 47 exons (46 coding) plus three alternatively spliced coding exons that are refered to as 13b, 25b, and 36b accordingly to Rivière et al [2011]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. The HSAN-causing mutations in KIF1A are loss-of-function mutations including mutations in the alternatively spliced exon 25b, which is strongly expressed in the nervous system.

Table 5. Selected KIF1A Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReferences
c.2840delTp.Leu947ArgfsTer4Rivière et al [2011]
c.5271dupCp.Ser1758GlnfsTer7

Note on variant classification: Variants listed in the table have been provided by the author. 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.

Normal gene product. KIF1A is a multidomain protein with a kinesin motor domain, a Forkhead-associated domain, and the Pleckstrin homology domain. It belongs to the kinesin superfamily proteins (KIFs) which transports membranous organelles and macromolecules along microtubules. In the axons, precursors of synaptic vesicles are transported anterogradely by KIF1A.

Abnormal gene product. The mutations in KIF1A reported so far lead to protein truncations and/or nonsense-mediated mRNA decay compatible with loss of function.

References

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Chapter Notes

Revision History

  • 3 November 2011 (ik) HSAN2C, caused by mutations in KIF1A
  • 23 November 2010 (me) Review posted live
  • 14 July 2010 (ik) Original submission
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