Acta Dermato-Venereologica 99-10CompleteContent | Page 14
894
INVESTIGATIVE REPORT
Novel and Recurrent PNPLA1 Mutations in Spanish Patients with
Autosomal Recessive Congenital Ichthyosis; Evidence of a Founder
Effect
Uxia ESPERÓN-MOLDES 1,2 , Manuel GINARTE VAL 3 , Laura RODRÍGUEZ-PAZOS 4 , Laura FACHAL 1 , José Manuel AZAÑA 5 ,
María Barberá FONS 6 , Mónica VIEJO DIAZ 7 and Ana VEGA 1
1
Galician Public Foundation of Genomic Medicine (FPGMX)-SERGAS, Genomics Medicine Group-USC, CIBERER, IDIS, 2 Department of Forensic
Sciences, Pathological Anatomy, Gynecology, Obstetrics and Pediatrics, USC, 3 Dermatology Service of University Clinical Hospital of Santiago,
Santiago de Compostela, 4 Dermatology Service of University Clinical Hospital of Vigo, Vigo, 5D ermatology Service of Albacete University
Hospital Complex, Albacete, 6 Dermatology Service of University and Polytechnic Hospital La Fe, Valencia, and 7 Clinical Genetics Service of
Central University Hospital of Asturias, Oviedo, Spain
Autosomal recessive congenital ichthyosis is a group
of rare non-syndrome diseases that affect cornifica-
tion. PNPLA1 is one of the 12 related genes identified
so far. Mutation screening of this gene has resulted
in the identification of 13 individuals, from 10 fami-
lies, who carried 7 different PNPLA1 mutations. These
mutations included 2 missense, 2 frameshift and 3
nonsense, 3 of them being novel. One of the identified
variants, c.417_418delinsTC, was highly prevalent, as
it was found in 6 out of 10 (60%) of our autosomal
recessive congenital ichthyosis families with PNPLA1
mutations. Clinical manifestations varied significantly
among patients, but altered sweating; erythema, pal-
mar hyperlinearity and small whitish scales in flexor-
extensor and facial areas were common symptoms.
Haplotype analyses of c.417_418delinsTC carriers
confirmed the existence of a common ancestor. This
study expands the spectrum of the PNPLA1 disease,
which causes variants and demonstrates that the
c.417_418delinsTC mutation has founder effects in the
Spanish population.
Key words: ARCI; Spanish population; PNPLA1; founder
effects; c.417_418delinsTC.
Accepted May 22, 2019; E-published May 23, 2019
Acta Derm Venereol 2019; 99: 894–898.
Corr: PhD Ana Vega, Molecular Medicine Service, Fundación Pública Ga-
lega de Medicina Xenómica, University Hospital Santiago de Compostela,
floor -2, Santiago de Compostela, Spain. E-mail: [email protected]
N
umerous hereditary cornification disorders that are
clinically and aetiologically heterogeneous and
follow a Mendelian inheritance pattern are grouped
under the term of inherited ichthyosis. Autosomal re-
cessive congenital ichthyosis (ARCI) are a subgroup of
non-syndrome ichthyosis, whose phenotypic spectrum
ranges from harlequin ichthyosis (HI; OMIM 242500),
to less severe phenotypes such as congenital ichthyosi
form erythroderma (CIE; OMIM 242100) or lamellar
ichthyosis (LI; OMIM 242300) the last two being the
most common phenotypes. To date, 12 genes have
been implicated in the development of ARCI: ABCA12,
doi: 10.2340/00015555-3227
Acta Derm Venereol 2019; 99: 894–898
SIGNIFICANCE
Due to the growing importance of PNPLA1 mutations in the
development of autosomal recessive congenital ichthyosis
(ARCI), we decided to sequence this gene in a large, well-
characterized cohort of Spanish ARCI patients. The muta-
tional analysis revealed 7 different PNPLA1 mutations, 3
of which were novel, in 13 individuals from 10 families.
Interestingly, one of the identified mutations was present
in 60% of the families (c.417_418delinsTC; p.Ser140Pro).
Haplotype analysis of the c.417_418delinsTC carriers de
monstrated that these families are descendants of a recent
founder who lived in the XI century, implying that this re-
current mutation has founder effects in the Spanish popu-
lation.
ALOX12B, ALOXE3, CYP4F22, NIPAL4, TGM1, LIPN
and more recently CERS3, PNPLA1, CASP14, SDR9C7
and SULT2B1 (1–3).
PNPLA1 is a gene that encodes a 58 kDa protein
involved in the glycerophospholipid metabolism of the
cutaneous barrier. Forty-seven disease causing muta-
tions have been described in PNPLA1 so far (4–12),
the majority of which were reported within the last two
years (4–9, 11, 12). Due to the growing importance
of PNPLA1 mutations in the development of ARCI,
we decided to screen for PNPLA1 defects in a large,
well-characterized cohort of individuals with ARCI.
Screening has resulted in the identification of a recur-
rent variant, c.417_418delinsTC, which was present
in approximately half of our families. Given the high
prevalence of this mutation among our Spanish patients,
we tested the hypothesis that this mutation arose in a
founder ancestor in the distant past.
Thus, the aims of this study are: (i) to report new cau-
sative PNPLA1 mutations in a Spanish cohort of patients
with ARCI, (ii) to computationally assess the effect of
the recurrent c.417_418delinsTC mutation on protein
function, (iii) to evaluate whether families who carry
this variant share a common ancestor and, if so, (iv) to
estimate the time to their most recent common ancestor
(TMRCA) and the age of the mutation.
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2019 Acta Dermato-Venereologica.