Research Article
What can we learn from the Distribution of the 2.7kb Deletion Mutation of the OCA2 Gene in Oculocutaneous Albinism Type 2 (OCA2) in Cameroon and in Sub-Saharan Countries?
Robert Aquaron1*, Jean-Louis Berge-Lefranc2, Eulalie Lassaux3,
Claudio Plaisant3, Benoit Arveiler3,5 and Murray Brilliant4
1Timone Health Campus, Aix-Marseille University, France
2Laboratory of Molecular Biology, Conception Hospital, France
3Department of Medical Genetics, Bordeaux University Hospital, France
4Center for Precision Medicine Research, Marshfield Clinic Research Institute, USA
5University of Bordeaux, Rare Diseases: Genetics and Metabolism (MRGM), France
*Corresponding author: Robert Aquaron, Timone Health Campus, Aix-
Marseille University, Boulevard Jean Moulin, 13385, Marseille, France, Tel: 33-06-1374-0767; Email:
robert.aquaron@univ-amu.fr
Submitted: 08 February 2019; Accepted: 18 April 2019; Published: 19 April 2019
Cite this article: Aquaron R, Berge-Lefranc JL, Lassaux E, Plaisant C, Arveiler B, et al. (2019) What can we learn from the Distribution of the 2.7kb Deletion
Mutation of the OCA2 Gene in Oculocutaneous Albinism Type 2 (OCA2) in Cameroon and in Sub-Saharan Countries? JSM Dermatolog Clin Res 1: 5.
The specific African intragenic deletion of the 2.7-kb of the OCA2 gene was determined in a 408 OCA2 patients from Cameroon
with an allele frequency of 0.68, a value close to that found in other Bantu-speaking countries located in central, south and east Africa.
We observed a lack of this mutation in 30 non-Bantu-speaking OCA2 patients from West Africa countries. This mutation is associated in
Cameroonian OCA2 subjects with a specific TAG haplotype allowing us to estimate that this mutation originated 4,100-5,645 years ago
probably in the original Bantu homeland situated in the present day at the border Nigeria-Cameroon. The eastern wave of expansion and
migration of Bantu-speaking peoples from their homeland was studied by comparing haplotype analysis using 4 intragenic microsatellites
markers of OCA2 subjects from Cameroon and Democratic Republic of Congo. The haplotype 232-156 was present at frequency 1.0
in Cameroonian OCA2 patients and 0.87 in OCA2 DRC subjects suggesting that this haplotype is originating from Cameroon and was
diluted during the migration process by genetic contribution of neighbouring populations. Finally we show that when this mutation was at
homozygous state, the skin dendritic freckles were always absent, characterizing the phenotype OCA2a.
Keywords: OCA2; 2.7kb deletion; Sub-Saharan Africa; Cameroon; Bantu
OCA: Oculo Cutaneous Albinism; TYR: Tyrosinase, TYRP1:
Tyrosinase Related Protein 1; SLC: Solute Carrier; P: Pinkeye
dilution; ER: Endothelial Reticulum; CAR: Central African
Republic; DRC: Democratic Republic of Congo; RC: Republic of
Congo; SNP: Single Nucleotide Polymorphism; DF: Dendritic
Freckles
Oculocutaneous Albinism (OCA) is a rare genetic disease
characterized by generalized hypopigmentation of the skin, hair and eyes causing multiple ophthalmologic abnormalities
(decreased visual acuity, nystagmus, light sensitivity) and
impaired eye development (incomplete development of the
fovea and changes in axonal routing in the optic nerve and
tracts). OCA is a genetically heterogeneous group of autosomal
recessive disorders caused by deficiency of melanin biosynthesis
or melanin transport. Melanin is a polymeric pigment produced
in specialized ectodermally derived cells called melanocytes and
in organelles called melanosomes. There are four common forms
of non-syndromic OCA in which the manifestations are limited to
skin, hair and eye function: OCA1, OCA2, OCA3 and OCA4 named
after their date of the mutations discovered respectively in genes
TYR, OCA2, TYRP1 and SLC45A2. OCA2 is caused by mutations in
the OCA2 gene (formerly called P gene) on Chromosome 15q12
that contains 25 exons. The encoded protein is predicted to
have a 12-transmembrane domains and functions as a chloride
transporter [1]. However disruption of the function of P gene
causes the aberrant trafficking of TYR, the key enzyme required
for melanin synthesis, to melanosomes after its processing
through the ER and Golgi [2].
OCA2 is the most common type of OCA among Africans
and African-Americans. There is a high incidence of OCA2
among specific African populations mainly in sub-Saharan
countries located in south, central and east Africa. A specific
intragenic deletion of 2.7kb of the OCA2 gene lacking exon 7 has
been described in 1994 [3]. This mutation, at homozygous or
heterozygous state, was found in four unrelated African-American OCA2 patients, in two African OCA2 patients from Cameroon and
DRC, but not in Caucasians with OCA2. This finding indicates an
African origin for this allele and was confirmed in several studies [4-13].
The aims of this work are a) to recapitulate our research on
the frequency of this mutation mainly in Cameroon and in some
other African countries (Burundi, DRC, RC) in comparison with
the findings in other African countries, b) to postulate that the
haplotypes associated with this deletion could be utilized as a
biological marker for the migration of Bantu-speaking people
and c) that individuals who are homozygous for this mutation
correspond to the subtype, OCA2a, characterized by the absence
of dendritic freckles.
We analyzed 459 OCA2 patients from different countries
(Cameroon, CAR, DRC, RC, Burundi) for the 2.7kb deletion study.
We analyzed 27 OCA2 patients from Cameroon and 38 from
DRC for the haplotype study. We analyzed 124 OCA2 patients
from Cameroon and Tanzania for the OCA2a and OCA2b study.
Informed written and/or oral consent was obtained from the
patients. For each patient a clinical data sheet with skin and
ophthalmologic findings was performed. PCR analysis of the 2.7
kb deletion was performed using either semi-quantitative PCR or
qualitative PCR [14] Haplotype analysis of the OCA2 locus was
performed using four intragenic microsatellite markers located
respectively in Introns 2, 17, 20 and 22: OCAI-2, OCAI-17, OCAI-
20 and OCAI-22
a) Since 1973, we have been focused on understanding OCA
in Cameroon and particularly by OCA2 which is the most frequent
type of albinism in this country, in Sub-Saharan countries and in African-Americans resulting from the Atlantic slave trade.
Since the discovery in 1994 [3] of the specific African intragenic
deletion of 2.7-kb of the OCA2 gene in OCA2 Africans (Cameroon,
DRC) and in African-Americans, we have been able to easily
detect this specific mutation at homozygous or heterozygous
state or its absence among OCA2 patients from Cameroon and
other Sub-Saharan countries (Burundi, CAR, DRC and RC). The
genotypic status and the allele frequency of this mutation are
summarized in Table 1. Among a total of 730 OCA2 Cameroonian
patients examined, we performed analysis of the deletion allele
respectively in 36, 173 and 408 individuals showing respectively
an allele frequency of 0.65 [8]; 0.67 [10] and 0.68 [13]. In the 408
patients study we reported separately results from the principal
ethnic group, the Bamileke tribe with an allele frequency of 0.55
among 213 subjects [13]. Off the 195 individuals of different
ethnic groups (Bamoun, Bassa, Beti, Douala, Ewondo) the allele
frequency was 0.80 resulting in a median value of 0.68 for
Cameroon. As a whole the allele frequency in some central, south
and east Africa countries was around 0.70 (Cameroon: 0.68;
Burundi: 0.73; DRC: 0.76; South Africa and Tanzania: 0.77; Zambia:
0.79) culminating with 0.94 in Zimbabwe (Figure 1). The low
values found in CAR (0.31) and in RC (0.25) may result from the
paucity of analyzed patients 2 and 8 respectively. This mutation
was also found in African- Americans from USA and Haiti [3,4]
with a low allele frequency 7/24= 0.29 due to the low number
of subjects (12) but also due to the fact that the Atlantic slave
trade has occurred mainly ( >55%) from West Africa where the
population is predominantly negroid [15]. These findings were
in accordance with our results: a lack of this mutation in 30 non
Bantu-speaking OCA2 individuals from West African countries:
17,10,1,1 and 1 respectively from Mali , Niger, Nigeria, Togo and
Burkina-Faso. Another child with OCA2 from Nigeria lacking this
mutation has also been reported [6]. The high frequency of the deletion allele could be due to a selective advantage enjoyed by the
heterozygotes or as a result of genetic drift or by some unknown
selective force. It has also been hypothesised that carriers of
this mutation may have a protective advantage from infection
with leprosy [16]. This mutation was associated predominantly
in Southern Africa [7] with one common haplotype determined
by Southern blot of genomic DNA (A: 0.78). Subsequently using
a five SNP assay we identified in 53 OCA2 Cameroonian [11]
a common TAG haplotype with frequency of 1.0. This study
allowed us to estimate that this mutation originated 4,100-
5,645 years ago. These findings showed that this mutation was
specific of Bantu speaking populations living in central, south
and east Africa. Anthropological and archaeological data seem to
indicate that original Bantu homeland is situated in the present
day at border Nigeria-Cameroon near the Benoue River [17].
Linguistic and genetic data fit well with a scenario of dispersal
and expansion of Bantu from their homeland around 5,000 years
ago. Genetic data were based on uniparental markers: mtDNA for
females and Y chromosomes for males [18-20]. The expansion of
Bantu speaking peoples occurred in two directions: the southernwestern
wave moved mostly through the coast, the riverine sites
then to east; the eastern wave involved the settlement of farmers
in a region which is now Uganda, then to the great lake region,
then to south and west (Figure 2). The two waves of expansion
are thought to have met around 2.000 years ago, in the region
now known as Zimbabwe. Today the migration process is still
in progress. We had the opportunity to analyze a Bantu family
with 2 children with OCA2 carrying the 2.7-kb mutation at
homozygous state in Reunion island [21]. Reunion Island is a
French overseas “department” located in the western Indian
Ocean, off the eastern coast of Madagascar. In fact this family was
originated from Mayotte, an island from the Comoros archipelago
located northwest of Madagascar and probably from east Africa
coast [22] (Figure 2).
-
Table 1:Genotype status and allele frequencies of the 2.7-kb deletion of the OCA2 gene in OCA2 patients from different countries in east, south and
central Africa (n: number of individuals), D, Deletion mutation, O, Other mutation, CAR, Central African Republic, DRC, Democratic Republic of Congo,
RC, Republic of Congo. View Table
-
Figure 2:Bantu homeland, migration and expansion. Bantu tag refers
to the assumed original Bantu area at border Nigeria- Cameroon near
the Benoue River. Filled arrows refer to the eastern Bantu waves
with settlement of farmers in the interlacustrine region which is now
Uganda. Then the expansion was directed south in three distinct
waves, one travelling along the coast (blue arrows) , the second going
to Comoros archipelago and Madagascar island and the third one
going through west. Dotted arrows refer to the southward western
waves moving through the coast then east. The two major waves
(filled and dotted arrows) are thought to have met in the region now
known as Zimbabwe (adapted from [18,19]). View Figure
b) In addition to the classical genetic markers (mtDNA and
Y chromosomes) utilized for the study of Bantu migration, we
have shown that the frequency of the 2.7-kb deletion allele
is around 0.70 in the homeland of Bantus, Cameroon and in
countries located on the eastern wave: DRC, Burundi, Tanzania, Zambia and South Africa. The fact that Zimbabwe presented the
highest allele frequency rate of 0.94 could be in accordance with
the postulated meeting point of the 2 waves. We hypothesised
that this mutation and new associated haplotypes in two of these
countries (Cameroon and DRC) could be a marker of the eastern
wave. We performed a haplotype analysis encompassing the
OCA2 gene using four intragenic micro satellite markers: OCAI-
2, OCAI-17, OCAI-20 and OCAI-22. The haplotype 232-156-193-
147 was the only haplotype associated with the 2.7-kb deletion
in Cameroonian albinos. The OCAI-2-OCAI-17 haplotype 232-
156 was present at frequency of 1.0 (44/44 alleles) in 22 OCA2
Cameroonian and 0.87 (58/68 alleles) in 34 OCA2 Congolese
(DRC). In DRC albino beside this haplotype other OCAI-2-OCAI-17
haplotypes were found: 230-162, 230-168. These differences
were probably due to different genetic contributions from
neighbouring populations during the migration process.
c) OCA2 individuals in southern Africa presented with two
distinct phenotypes: affected individuals are characterized
by the presence or absence of pigmented patches (ephelides)
mainly on sun exposed areas [5]. The correlation between
the 2 phenotypes and the deletion allele frequency showed a
significant difference using the khi2 test (P<.0001): 0.89 (n: 24)
for individuals without ephelides and 0.54 (n: 38) for those with
ephelides. These pigmented skin lesions have been later clinically
carefully described as dendritic freckles characterized by
irregular branched shape, light to brown- black colour and large
size (0.5 to 3.0cm). They appear only at the age 5-10 years [23].
These two phenotypes are now called: OCA2a without freckles
and OCA2b with such freckles [24]. In a recent work we have
found different results in a large cohort of 124 OCA2 individuals
from Cameroon and Tanzania [25]. When the 2.7- kb deletion
was present at homozygous state (84 OCA2 patients) DF were
always absent. When the 2.7-kb deletion was at heterozygous
state and the second mutation was a nonsense mutation like
R165X, DF was also absent (3 Cameroonian patients). If the
second mutation is a missense mutation like P221L we observe
DF. We could hypothesise that when the mutations are deletions
or nonsense, inactivation of the gene was total and irreversible
and DF was always absent. In the case of missense mutations, the
mutation can mutate back to normal in some melanocytes with
sun damage leading to DF. This hypothesis is in good correlation
with the fact that DF appears only at age 8-10 after sun exposure
which is particularly important in Sub-Saharan Africa.
We have shown that the specific African intragenic deletion
of 2.7-kb of the OCA2 gene is present at a high allele frequency,
around 0.70 in OCA2 individuals in many countries from east,
south and central Africa but not in west Africa. It could be utilized
as a genetic marker to follow the expansion and migration of
Bantus from their homeland Cameroon, to south and east African
countries. We have also shown that this mutation at homozygous
state characterized the phenotype OCA2a where the skin
dendritic freckles are absent.
We thank all the volunteers from Cameroon, Burundi,
DRC and Tanzania who participated in this study, Dr. Frederic
Ntwengarubum from Bujumbura Burundi, Pr. Leon Tshilolo and
Mwimba Texas from Kinshasa, DRC, Servain and Jeanjanvier
Ndumba from Kisangani, DRC, Luc Kamdem from Yaounde and
Hugues Ngando from Douala, Cameroon, for help with patients
recruitment and blood samples supply. We also thank Ghislaine
Hancy for help to preparing the manuscript. This work was
supported by Genespoir (French Albinism Association).