A new splice-site mutation in <i>SLC12A6</i> causing Andermann syndrome with motor neuronopathy

Akçakaya, Nihan Hande; Yapıcı, Zühal; Tunca, Ceren; Tektürk, Pınar; Akçimen, Fulya; Başak, A. Nazlı

doi:10.1136/jnnp-2017-317319

Cited by 4 publications

(4 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The central importance of fine‐tuning KCC3 activity in neuronal cells is highlighted by the finding that peripheral nerve degeneration occurs for both gain‐of‐function (GOF) and loss‐of‐function (LOF) mutations in the human SLC12A6 gene (Flores et␣al, 2019). The recessive Mendelian disorder HMSN/ACC (also known as Andermann syndrome) is caused by a range of different frameshift and premature termination mutations, resulting in complete loss of transport function (Uyanik et␣al, 2006; Akcakaya et␣al, 2018). The recently discovered GOF mutation T991A in KCC3, which results in severe motor neuropathy (Kahle et␣al, 2016), occurs in one of the two canonical phospho‐regulatory residues (T991 and T1048 in the A‐isoform and T940 and T997 in the B‐isoform) that are crucial for phospho‐inhibition.…”

Section: Introductionmentioning

confidence: 99%

Phospho‐regulation, nucleotide binding and ion access control in potassium‐chloride cotransporters

et al. 2021

View full text Add to dashboard Cite

Potassium-coupled chloride transporters (KCCs) play crucial roles in regulating cell volume and intracellular chloride concentration. They are characteristically inhibited under isotonic conditions via phospho-regulatory sites located within the cytoplasmic termini. Decreased inhibitory phosphorylation in response to hypotonic cell swelling stimulates transport activity, and dysfunction of this regulatory process has been associated with various human diseases. Here, we present cryo-EM structures of human KCC3b and KCC1, revealing structural determinants for phosphoregulation in both N-and C-termini. We show that phosphomimetic KCC3b is arrested in an inward-facing state in which intracellular ion access is blocked by extensive contacts with the N-terminus. In another mutant with increased isotonic transport activity, KCC1D19, this interdomain interaction is absent, likely due to a unique phospho-regulatory site in the KCC1 N-terminus. Furthermore, we map additional phosphorylation sites as well as a previously unknown ATP/ADP-binding pocket in the large Cterminal domain and show enhanced thermal stabilization of other CCCs by adenine nucleotides. These findings provide fundamentally new insights into the complex regulation of KCCs and may unlock innovative strategies for drug development.

show abstract

Section: Introductionmentioning

confidence: 99%

Phospho‐regulation, nucleotide binding and ion access control in potassium‐chloride cotransporters

et al. 2021

View full text Add to dashboard Cite

show abstract

“…When cell is faced to the hypotonic circumstances, dephosphorylated KCCs induce the potassium and chloride ions efflux to the extracellular space, promoting cell shrink to the normal volume (11). Disorder of the SLC12 family results in hereditary diseases including epilepsy (12,13), Anderman syndrome (14), Gitelman syndrome (15), Bartter syndrome (16), and deafness (17,18). KCC2, which was identified in 1996 from rat brain cDNA library, is restrictedly expressed in central nervous system (19).…”

Section: Introductionmentioning

confidence: 99%

Molecular basis for regulation of human potassium chloride cotransporters

Chi

Chen

et al. 2020

Preprint

View full text Add to dashboard Cite

The Solute Carrier Family 12 (SLC12) encodes electroneutral cation-chloride cotransporters (CCCs) that are fundamental in cell volume regulation and chloride homeostasis. Dysfunction of CCCs engenders abnormality in renal function and neuro-system development. Here we presented structure of the full length human potassium-chloride co-transporter 2 (KCC2) and 3 (KCC3), the KCC3 mutants in phosphorylation mimic (P-mimic) and dephosphorylation mimic (DP-mimic) status, and KCC3 in complex with [(DihydroIndenyl)Oxy] Alkanoic acid (DIOA), a specific inhibitor of KCCs, at resolution of 2.7 Å -3.6 Å. A small N-terminal loop is bound at the intracellular vestibule of the transport path, arresting the transporter in an autoinhibition state. The C-terminal domain (CTD) of KCCs is structure-solved for the first time, revealing two conserved phosphorylation harboring segments (PHSs), which exhibit different conformation between P-mimic and DP-mimic mutants, explaining the inhibitory effect of phosphorylation. DIOA is located in between the two transmembrane domains, tightly bound to the loop between TM10 and TM11, locking the transporter in inward-facing conformation. Together, our study makes important steps in understanding the sophisticated regulation mechanisms of KCCs, with prospect for the specific drug development.

show abstract

“…ACC might absent, as stated above. Unsolved cases of motor neuropathy with presentation like spastic paraplegia. A new mutation has been published recently where the clinical picture mimicked spastic paraplegia without involvement of the sensory nerves (Akcakaya et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…This high prevalence was shown to be caused by a single founder mutation (p.Thr813fsX813 in the 18th exon; De Braekeleer et al, ; Dupre et al, ). Besides this area of relatively high prevalence, AS is reported occasionally in patients from other countries (Turkey, Germany, Pakistan, Italy, Austria, Sudan, Tansania, Algeria), in most instances occurring in Turkey (6 of 13 families; Akcakaya et al, ; Degerliyurt, Akgumus, Caglar, Bilguvar, & Caglayan, ; Deleu, Bamanikar, Muirhead, & Louon, ; Hauser, Bittner, Liegl, Bernert, & Zeitlhofer, ; Lesca et al, ; Lourenco et al, ; Muñoz, Krishnan, Vajsar, Laughlin, & Yoon, ; Rudnik‐Schoneborn et al, ; Salin‐Cantegrel et al, ; Uyanik et al, ). None of the described patients were of Roma ethnic origin.…”

Section: Introductionmentioning

confidence: 99%

First case of Roma ethnic origin with Andermann syndrome: A novel frameshift mutation in exon 20 of SLC12A6 gene

Pacheva

Todorov

Halil

et al. 2019

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Andermann syndrome (AS) is caused by mutation of SLC12A6 gene. It comprises severe progressive sensory and motor neuropathy with early onset, varying degree of agenesis of corpus callosum (ACC) and mental retardation. AS occurs occasionally among population outside the northeastern Quebec-Saguenay-Lac-St-Jean and Charlevoix regions, inhabited by French Canadians. None of the described patients were of Roma ethnic origin. We present an 8-month-old infant of Roma ethnic origin with AS, caused by a novel frame shift mutation c.2604delT,p.(Asp868GlufsTer11) in exon 20 of SLC12A6 gene. Our case presented with several atypical findings: clinical presentation resembling "spinal muscular atrophy plus" syndrome; tongue fasciculations, which are not reported in the literature; early contractures of the wrists; normal motor action potentials and preserved sensory action potentials.Our patient is the first of Roma origin from nonconsanguineous parents, which suggests that this mutation might be widespread in the Roma population, although screening for this mutation in 140 alleles from Roma individuals originating from the same geographic region did not reveal further carriers, implying the mutation is rare. We recommend that Roma patients presenting with the clinical phenotype of AS should be tested for this mutation primarily. K E Y W O R D S agenesis of corpus callosum, Andermann syndrome, hereditary neuropathy, Roma population, SLC12A6 gene

show abstract

A new splice-site mutation in SLC12A6 causing Andermann syndrome with motor neuronopathy

Cited by 4 publications

References 4 publications

Phospho‐regulation, nucleotide binding and ion access control in potassium‐chloride cotransporters

Phospho‐regulation, nucleotide binding and ion access control in potassium‐chloride cotransporters

Molecular basis for regulation of human potassium chloride cotransporters

First case of Roma ethnic origin with Andermann syndrome: A novel frameshift mutation in exon 20 of SLC12A6 gene

Contact Info

Product

Resources

About